Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors

ABSTRACT

This invention relates to substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors, to pharmaceutical compositions comprising such compounds, and to methods of using these compounds for treating viral infection. A representative compound of the invention is the compound of formula: ##STR1## wherein R 22  and R 23  are allyl.

CROSS-REFERENCE TO EARLIER FILED APPLICATIONS

This is a division of application Ser. No. 08/197,630, filed Feb. 16,1994, now U.S. Pat. No. 5,610,294 which is a continuation-in-part ofU.S. patent application Ser. No. 08/047,330, filed Apr. 15, 1993,abandoned which is a continuation-in-part of U.S. patent applicationSer. No. 08/023,439, filed Feb. 26, 1993, abandoned which is acontinuation-in-part of U.S. patent application Ser. No. 07/953,272,filed Sep. 30, 1992, abandoned which is a continuation-in-part of U.S.patent application Ser. No. 07/883,944, filed May 15, 1992, abandonedwhich is a continuation-in-part of U.S. patent application Ser. No.07/776,491, filed Oct. 11, 1991 abandoned. The disclosure of theseearlier filed applications is hereby incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to substituted cyclic carbonyls and derivativesthereof useful as retroviral protease inhibitors, to pharmaceuticalcompositions comprising such compounds, and to methods of using thesecompounds for treating viral infection.

BACKGROUND OF THE INVENTION

Current treatments for viral diseases usually involve administration ofcompounds that inhibit viral DNA synthesis. Current treatments for AIDS(Dagani, Chem. Eng. News, Nov. 23, 1987 pp. 41-49) involveadministration of compounds such as 2',3'-dideoxycytidine, trisodiumphosphonoformate, ammonium 21-tungsto-9-antimoniate,1-b-D-ribofuranoxyl-1,2,4-triazole-3-carboxamide,3'-azido-3'-deoxythymidine (AZT), and adriamycin that inhibit viral DNAsynthesis; compounds such as AL-721 and polymannoacetate which mayprevent HIV from penetrating the host cell; and compounds which treatthe opportunistic infections caused by the immunosuppression resultingfrom HIV infection. None of the current AIDS treatments have proven tobe totally effective in treating and/or reversing the disease. Inaddition, many of the compounds currently used to treat AIDS causeadverse side effects including low platelet count, renal toxicity, andbone marrow cytopenia.

The genomes of retroviruses encode a protease that is responsible forthe proteolytic processing of one or more polyprotein precursors such asthe pol and gag gene products. See Wellink, Arch. Virol. 98 1 (1988).Retroviral proteases most commonly process the gag precursor into thecore proteins, and also process the pol precursor into reversetranscriptase and retroviral protease.

The correct processing of the precursor polyproteins by the retroviralprotease is necessary for the assembly of the infectious virions. It hasbeen shown that in vitro mutagenesis that produces protease-defectivevirus leads to the production of immature core forms which lackinfectivity. See Crawford et al., J. Virol. 53 899 (1985); Katoh et al.,Virology 145 280 (1985). Therefore, retroviral protease inhibitionprovides an attractive target for antiviral therapy. See Mitsuya, Nature325 775 (1987).

Moore, Biochem. Biophys. Res. Commun., 159 420 (1989) discloses peptidylinhibitors of HIV protease. Erickson, European Patent Application No. WO89/10752 discloses derivatives of peptides which are inhibitors of HIVprotease.

U.S. Pat. No. 4,652,552 discloses methyl ketone derivatives oftetrapeptides as inhibitors of viral proteases. U.S. Pat. No. 4,644,055discloses halomethyl derivatives of peptides as inhibitors of viralproteases. European Patent Application No. WO 87/07836 disclosesL-glutamic acid gamma-monohydroxamate as an antiviral agent.

The ability to inhibit a viral protease provides a method for blockingviral replication and therefore a treatment for viral diseases, such asAIDS, that may have fewer side effects, be more efficacious, and be lessprone to drug resistance when compared to current treatments.

The present invention concerns novel substituted cyclic carbonyls andderivatives thereof, which compounds are capable of inhibiting viralprotease and which compounds are believed to serve as a means ofcombating viral diseases, such as AIDS. The substituted cyclic carbonylsand derivatives thereof of this invention provide significantimprovements over protease inhibitors that are known in the art. A largenumber of compounds have been reported to be inhibitors of proteases,such as renin, but these have suffered from lack of adequatebioavailability and are thus not useful as therapeutic agents,particularly if oral administration is desired. This poor activity hasbeen ascribed to the relatively high molecular weight of most proteaseinhibitors, to inadequate solubility properties, and to the presence ofa number of peptide bonds, which are vulnerable to cleavage by mammalianproteases in vivo and which generally cause the molecules to beextensively bound in human serum. The substituted cyclic carbonyls andderivatives described herein have a distinct advantage in this regard,in that they do not contain peptide bonds, are of low molecular weight,and can be hydrophilic yet still inhibit the viral protease enzyme.

Additionally, known inhibitors of other non-HIV proteases do not inhibitHIV protease. The structure-activity requirements of such inhibitorsdiffer from those of HIV protease inhibitors. The substituted cycliccarbonyls and derivatives of the invention are particularly useful asinhibitors of HIV protease and similar retroviral proteases.

The compounds of the invention are of low molecular weight and may,therefore, have good oral absorption properties in mammals.

SUMMARY OF THE INVENTION

This invention provides novel substituted cyclic carbonyl compounds andderivatives thereof, of formula (I) (described below) which are usefulas inhibitors of Human Immunodeficiency Virus (HIV). The compounds ofthe present invention inhibit the HIV protease and thereby inhibit HIVreplication. The present invention also includes pharmaceuticalcompositions containing such compounds of formula I, and methods ofusing such compounds for the inhibition of HIV in a sample containingHIV, and methods of using such compounds for the treatment of HIVinfection in a patient.

The present invention also includes methods of inhibiting HIV ortreating HIV infection by administering a compound of formula (I) incombination with one or more second therapeutic agents selected fromother inhibitors of HIV and/or therapeutic agents for the treatment ofHIV-mediated disease conditions.

Also included in the present invention are pharmaceutical kitscomprising one or more containers containing pharmaceutical dosage unitscomprising a compound of formula I, for the treatment of HIV infection.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides novel substituted cyclic carbonyl compounds andderivatives thereof, of formula (I) (described below) which are usefulas inhibitors of Human Immunodeficiency Virus (HIV). The compounds ofthe present invention inhibit the HIV protease and thereby inhibit HIVreplication. The present invention also includes pharmaceuticalcompositions containing such compounds of formula I, and methods ofusing such compounds for the inhibition of HIV in a sample containingHIV, and methods of using such compounds for the treatment of HIVinfection in a patient.

1! There is provided by this invention a compound of the formula (I):##STR2## or a pharmaceutically acceptable salt or prodrug form thereofwherein: R⁴ and R⁷ are independently selected from the following groups:

hydrogen;

C₁ -C₈ alkyl substituted with 0-3 R¹¹ ;

C₂ -C₈ alkenyl substituted with 0-3 R¹¹ ;

C₂ -C₈ alkynyl substituted with 0-3 R¹¹ ;

a C₃ -C₁₄ carbocyclic ring system substituted with 0-3 R¹¹ or 0-3 R¹² ;

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R¹² ;

--OR¹³ ; --SR¹³ ; CO₂ R¹³ ;

R^(4A) and R^(7A) are independently selected from the following groups:

hydrogen;

C₁ -C₄ alkyl substituted with 0-6 halogen or 0-3 C₁ -C₂ alkoxy;

benzyl substituted with 0-6 halogen or 0-3 C₁ -C₂ alkoxy;

--OR¹³ ; --SR¹³ ; CO₂ R¹³ ;

R⁴ and R^(4A) can alternatively join to form a 5-7 membered carbocyclicring substituted with 0-2 R¹² ;

R⁷ and R^(7A) can alternatively join to form a 5-7 membered carbocyclicring substituted with 0-2 R¹² ;

n is 0, 1, or 2;

R⁵ is selected from H; halogen; C₁ -C₆ alkyl substituted with 0-3 R¹¹ ;--N(R²⁰)₂ ; --SR²⁰ ; or --OR²⁰, --N₃ ;

R⁶ is independently selected from: hydrogen, halogen, C₁ -C₆ alkylsubstituted with 0-3 R¹¹, --N(R²⁰)₂, --SR²⁰, or --OR²¹, --N₃ ;

R⁵ and R⁶ can alternatively join to form an epoxide or aziridine ring;--OCH₂ SCH₂ O--; --OC(═O)O--; --OCH₂ O--; --OC(═S)O--; --OC(═O)C(═O)O--;--OC(CH₃)₂ O--; --OC((CH₂)₃ NH₂) (CH₃)O--; --OC(OCH₃) (CH₂ CH₂ CH₃)O--;--OS(═O)O--; --NHC(═O)NH--; --OC(═O)NH--; --NHC(═O)O--; --NHCH₂ O--;--OCH₂ NH--; --NHC(═S)O--; --OS(═O)NH--; --NHC(═O)C(═O)O--;--OC(═O)C(═O)NH--; --NHC(═O)C(═O)NH--; --NHC(CH₃)₂ O--; --OC(CH₃)₂ NH--or any group that, when administered to a mammalian subject, cleaves toform a free dihydroxyl or diamino or hydroxyl and amino;

R^(5a) is selected from hydrogen, halogen, C₁ -C₆ alkyl, --N(R²⁰)₂,--SR²⁰, or --OR²⁰ ;

R^(6a) is selected from: hydrogen, halogen, C₁ -C₆ alkyl, --N(R²⁰)₂,--SR²⁰ or --OR²¹ ;

R⁵ and R^(5a) can alternatively join to form ═O, ═S, or a ketal ring;

R⁶ and R^(6a) can alternatively join to form ═O, ═S, or a ketal ring;

R²⁰ and R²¹ are independently selected from:

hydrogen;

C₁ -C₆ alkyl substituted with 0-3 R¹¹ ;

C₃ -C₆ alkoxyalkyl substituted with 0-3 R¹¹ ;

C₁ -C₆ alkylcarbonyl substituted with 0-3 R¹¹ ;

C₁ -C₆ alkoxycarbonyl substituted with 0-3 R¹¹ ;

C₁ -C₆ alkylaminocarbonyl substituted with 0-3 R¹¹ ;

benzoyl substituted with 0-3 R¹² ;

phenoxycarbonyl substituted with 0-3 R¹² ;

phenylaminocarbonyl substituted with 0-3 R¹² ; or

any group that, when administered to a mammalian subject, cleaves toform a free hydroxyl, amino or sulfhydryl;

R¹¹ is selected from one or more of the following:

H, keto, halogen, cyano, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, --CO₂ R¹³,--OC(═O)R¹³, --OR¹³, --S(O)_(m) R¹³, --NHC(═NH)NHR¹³, --C(═NH)NHR¹³,--C(═O)NR¹³ R¹⁴, --NR¹⁴ C(═O)R¹³, ═NOR¹⁴, --NR¹⁴ C(═O)OR¹⁴, --OC(═O)NR¹³R¹⁴, --NR¹³ C(═O)NR¹³ R¹⁴, --NR¹⁴ SO₂ NR¹³ R¹⁴ --NR¹⁴ SO₂ R¹³, --SO₂NR¹³ R¹⁴, --OP(O) (OR¹³)₂, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₃ -C₆cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C₇ -C₁₀arylalkyl, hydroxamic acid, hydrazide, boronic acid, sulfonamide,formyl, C₃ -C₆ cycloalkoxy, C₁ -C₄ alkyl substituted with --NR¹³ R¹⁴, C₁-C₄ hydroxyalkyl, methylenedioxy, ethylenedioxy, C₁ -C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁ -C₄ alkoxycarbonyl, pyridylcarbonyloxy, C₁ -C₄alkylcarbonyl, C₁ -C₄ alkylcarbonylamino, --OCH₂ CO₂ H,2-(1-morpholino)ethoxy, azido, or --C(R¹⁴)═N(OR¹⁴);

1-3 amino acids linked together via amide bonds, said amino acid beinglinked via the amine or carboxylate terminus;

C₃ -C₁₀ cycloalkyl substituted with 0-2 R¹² ;

C₁ -C₄ alkyl substituted with 0-2 R¹²

aryl(C₁ -C₃ alkyl)-, substituted with 0-2 R¹² ;

C₂ -C₆ alkoxyalkyl-, substituted with 0-2 R¹² ;

C₁ -C₄ alkylcarbonyloxy substituted with 0-2 R¹²,

C₆ -C₁₀ arylcarbonyloxy substituted with 0-2 R¹²,

a C₅ -C₁₄ carbocyclic residue substituted with 0-3 R¹² ;

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-3 R¹² ;

R^(11A) is selected from one or more of the following: H, keto, halogen,cyano, --CH₂ N(R^(13A))R(^(14A)), --N(R^(13A))R(^(14A)), --CO₂ H,--OC(═O)(C₁ -C₃ alkyl), --OH, C₂ -C₆ alkoxyalkyl, --C(═O)NH₂,--OC(═O)NH₂, --NHC(═O)NH₂, --SO₂ NH₂, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₃-C₁₀ cycloalkyl, C₃ -C₆ cycloalkylmethyl, benzyl, phenethyl, phenoxy,benzyloxy, nitro, C₇ -C₁₀ arylalkyl, hydroxamic acid, hydrazide, boronicacid, C₃ -C₆ cycloalkoxy, C₁ -C₄ alkyl substituted with --NH₂, C₁ -C₄hydroxyalkyl, methylenedioxy, ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄haloalkoxy, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄alkylcarbonyl, C₁ -C₄ alkylcarbonylamino, --OCH₂ CO₂ H,2-(1-morpholino)ethoxy, azido, aryl(C₁ -C₃ alkyl), a C₅ -C₁₄ carbocyclicresidue; a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system substituted with 0-3 R^(12A).

R¹², when a substituent on carbon, is selected from one or more of thefollowing:

phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro,cyano, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, C₇ -C₁₀arylalkyl, C₁ -C₄ alkoxy, --CO₂ H, hydroxamic acid, hydrazide, boronicacid, sulfonamide, formyl, C₃ -C₆ cycloalkoxy, --OR¹³, C₁ -C₄ alkylsubstituted with --NR¹³ R¹⁴, --NR¹³ R¹⁴, C₂ -C₆ alkoxyalkyleneoptionally substituted with --Si(CH₃)₃, C₁ -C₄ hydroxyalkyl,methylenedioxy, ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, C₁-C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl, C₁-C₄ alkylcarbonylamino, --S(O)_(m) R¹³, --SO₂ NR¹³ R¹⁴, --NHSO₂ R¹⁴,--OCH₂ CO₂ R¹³, 2-(1-morpholino)ethoxy, --C(R¹⁴)═N(OR¹⁴); or

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur;

or R¹² may be a 3- or 4-carbon chain attached to adjacent carbons on thering to form a fused 5- or 6-membered ring, said 5- or 6-membered ringbeing optionally substituted on the aliphatic carbons with halogen, C₁-C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, or --NR¹³ R¹⁴ ; or, when R¹² isattached to a saturated carbon atom, it may be ═O or ═S; or when R¹² isattached to sulfur it may be ═O.

R¹², when a substituent on nitrogen, is selected from one or more of thefollowing:

phenyl, benzyl, phenethyl, hydroxy, C₁ -C₄ hydroxyalkyl, C₁ -C₄ alkoxy,C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, --CH₂ NR¹³R¹⁴, --NR¹³ R¹⁴, C₂ -C₆ alkoxyalkyl, C₁ -C₄ haloalkyl, C₁ -C₄alkoxycarbonyl, --CO₂ H, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl,--C(R¹⁴)═N(OR¹⁴);

R^(12A), when a substituent on carbon, is selected from one or more ofthe following:

phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro,cyano, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, C₇ -C₁₀arylalkyl, C₁ -C₄ alkoxy, --CO₂ H, hydroxamic acid, hydrazide, boronicacid, sulfonamide, formyl, C₃ -C₆ cycloalkoxy, --OR¹³, C₁ -C₄ alkylsubstituted with --NH₂, --NH₂, --NHMe, C₂ -C₆ alkoxyalkyl optionallysubstituted with --Si(CH₃)₃, C₁ -C₄ hydroxyalkyl, methylenedioxy,ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, C₁ -C₄alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl, C₁ -C₄alkylcarbonylamino, --S(O)_(m) Me, --SO₂ NH₂, --NHSO₂ Me, --OCH₂ CO₂R¹³, 2-(1-morpholino)ethoxy, --C(═NOH)NH₂ ; or

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur;

or R^(12A) may be a 3- or 4-carbon chain attached to adjacent carbons onthe ring to form a fused 5- or 6-membered ring, said 5- or 6-memberedring being optionally substituted on the aliphatic carbons with halogen,C₁ -C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, or --NH₂ ; or, when R^(12A) isattached to a saturated carbon atom, it may be ═O or ═S; or when R¹² isattached to sulfur it may be ═O.

R^(12A), when a substituent on nitrogen, is selected from one or more ofthe following:

phenyl, benzyl, phenethyl, hydroxy, C₁ -C₄ hydroxyalkyl, C₁ -C₄ alkoxy,C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, --CH₂ NH₂,--NH₂, C₂ -C₆ alkoxyalkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxycarbonyl,--CO₂ H, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl, --C(═NOH)NH₂ ;

R¹³ is selected from:

H;

phenyl substituted with 0-3 R^(11A) ;

benzyl substituted with 0-3 R^(11A) ;

C₁ -C₆ alkyl substituted with 0-3 R^(11A) ;

C₂ -C₄ alkenyl substituted with 0-3 R^(11A) ;

C₁ -C₆ alkylcarbonyl substituted with 0-3 R^(11A) ;

C₁ -C₆ alkoxycarbonyl substituted with 0-3 R^(11A) ;

C₁ -C₆ alkylaminocarbonyl substituted with 0-3 R^(11A) ;

C₃ -C₆ alkoxyalkyl substituted with 0-3 R^(11A) ;

an amine protecting group when R¹³ is bonded to N;

a hydroxy protecting group when R¹³ is bonded to O;

R¹⁴ is hydrogen, hydroxy, C₁ -C₆ alkyl substituted with 0-3 groupsselected from OH, C₁ -C₄ alkoxy, halogen, NH₂, --NH(C₁ -C₄ alkyl), C₁-C₆ alkoxy, C₂ -C₆ alkenyl, phenyl, benzyl, an amine protecting groupwhen R¹⁴ is bonded to N, a hydroxy protecting group when R¹⁴ is bondedto O;

R¹³ and R¹⁴ can alternatively join to form --(CH₂)₄ --, --(CH₂)₅ --,--CH₂ CH₂ N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --;

R^(13A) and R^(14A) are independently selected from: H, C₁ -C₆ alkyl;

R^(13A) and R^(14A) can alternatively join to form --(CH₂)₄ --, --(CH₂)₅--, --CH₂ CH₂ N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --;

R¹⁵ is H or CH₃ ;

m is 0, 1 or 2;

W is selected from:

--N(R²²)C(⊚Z)N(R²³)--;

--OC(═Z)O--;

--N(R²²)C(═Z)O--;

--C(R²⁵)(R²⁶)C(═Z)C(R²⁷)(R²⁸)--;

--N(R²²)C(═Z)C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)C(═Z)O--;

--N(R²²)C(═Z)C(═Z)N(R²³)--;

--C(R²⁵)(R²⁶)C(F₂)C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)N(CH₃)(O)C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)N(OR²⁹)C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)C(═Z)S--;

--N(R²²)S(═Z')N(R²³)--;

--N(R²²)S(═Z')₂ N(R²³)--;

--N(R²²)P(═O) (R^(24a))N(R²³)--;

--C(R²⁵)(R²⁶)S(═Z')C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)S(═Z')₂ C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)P(═O)(R^(24a))C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)S(═Z')N(R²³)--;

--C(R²⁵)(R²⁶)S(═Z')₂ N(R²³)--;

--C(R²⁵)(R²⁶)S(═O)₂ O--;

--C(R²⁵)(R²⁶)P(═O)(R^(24a))N(R²³)--;

--C(R²⁵)(R²⁶)P(═O)(R^(24a))O--;

--C(R²⁵)C(F₂)C(═O)N(R²³)--;

--C(R²⁵)C(F₂)S(═O)₂ N(R²³)--;

--SC(═Z)--;

--C(R²⁵)(R²⁶)C(R³⁴)(R³⁵)C(R²⁷)(R²⁸)--;

--N(R²²)C(R³⁴)(R³⁵)N(R²³)--;

--N═C(R³⁶)N(R²³)--;

--N⁺ (R²²)═C(R³⁶)N(R²³)--;

--N(R²²)P(R^(24a))N(R²³)--;

--C(═Z)--;

--P(═O)(R^(24a))--;

--S(═Z')--;

--S(═Z')₂ --;

--N(R²²)C(═C(R^(36a))(R^(36b)))N(R²³)--

--N(R²²)C(═Z)N(R²³)C(═Z)--

wherein:

Z is O, S, NR²⁴ ;

Z' is O or NR²⁴ ;

R²² and R²³ are independently selected from the following:

hydrogen; --OR^(22a) ; --N(R^(22a))(R^(22b));

C₁ -C₈ alkyl substituted with 0-3 R³¹ ;

C₂ -C₈ alkenyl substituted with 0-3 R³¹ ;

C₂ -C₈ alkynyl substituted with 0-3 R³¹ ;

a C₃ -C₁₄ carbocyclic ring system substituted with 0-5 R³¹ or 0-5 R³² ;

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R³² ;

R^(22a) and R^(22b) are independently selected from the following:

hydrogen;

C₁ -C₈ alkyl substituted with 0-3 R³¹ ;

C₂ -C₈ alkenyl substituted with 0-3 R³¹ ;

C₂ -C₈ alkynyl substituted with 0-3 R³¹ ;

a C₃ -C₁₄ carbocyclic ring system substituted with 0-5 R³¹ or 0-5 R³² ;

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R³² ;

R²⁴ is selected from: hydrogen; hydroxy; amino; C₁ -C₄ alkyl; C₁ -C₄alkoxy; mono- or di-(C₁ -C₆ alkyl)amino; cyano; nitro; benzyloxy;--NHSO₂ aryl, aryl being optionally substituted with (C₁ -C₆)alkyl;

R^(24a) is selected from: hydroxy; amino; C₁ -C₄ alkyl; C₁ -C₄ alkoxy;mono- or di-(C₁ -C₆ alkyl)amino; cyano; nitro; benzyloxy; or phenoxy;

R²⁵ and R²⁷ are independently selected from the following:

hydrogen;

C₁ -C₈ alkyl substituted with 0-3 R³¹ ;

C₂ -C₈ alkenyl substituted with 0-3 R³¹ ;

C₂ -C₈ alkynyl substituted with 0-3 R³¹ ;

a C₃ -C₁₄ carbocyclic ring system substituted with 0-5 R³¹ or 0-5 R³² ;

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R³² ;

--OR¹³ ; --SR¹³ ;

R²⁶ and R²⁸ are independently selected from:

hydrogen;

halogen;

C₁ -C₄ alkyl substituted with 0-3 halogen or 0-3 C₁ -C₂ alkoxy;

benzyl substituted with 0-3 halogen or 0-3 C₁ -C₂ alkoxy;

--OR¹³ ; --SR¹³ ;

R²⁹ is selected from:

hydrogen;

C₁ -C₄ alkyl substituted with 0-3 halogen or 0-3 C₁ -C₂ alkoxy;

benzyl substituted with 0-3 halogen or 0-3 C₁ -C₂ alkoxy;

alternatively, R²², R²⁵, or R²⁶, independently, can join with R⁴ orR^(4A) to form a 5- or 6-membered fused heterocyclic ring or carbocyclicring substituted with 0-2 R¹², said heterocyclic ring containing 1-3heteroatoms independently selected from N, S, or O; or

alternatively, R²³, R²⁷, or R²⁸, independently, can join with R⁷ orR^(7A) to form a 5- or 6-membered fused heterocyclic ring or carbocyclicring substituted with 0-2 R¹², said heterocyclic ring containing 1-3heteroatoms independently selected from N, S, or O; or

alternatively, R²², R²⁵, R²⁶, R²³, R²⁷, R²⁸, R³⁴, or R³⁵ can join withR⁵ or R⁶ to form a 0- to 7-membered bridge to form a carbocyclic orheterocyclic ring, said bridge being substituted with 0-2 R¹² and saidbridge containing 0-3 heteroatoms independently selected from N, S, or O(i.e., a 0-membered bridge is formed when R²², R²⁵, R²⁶, R²³, R²⁷, R²⁸,R³⁴, or R³⁵ are taken together with R⁵ or R⁶ to form a direct bond);

alternatively R²⁸ or R²³ can join with R^(7A) to form a direct bond;

alternatively R²⁶ or R²² can join with R^(4A) to form a direct bond;

R³¹ is selected from one or more of the following:

keto, halogen, cyano, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, --CO₂ R¹³, --C(═O)R¹¹,--OC(═O)R¹³, --OR¹³, C₂ -C₆ alkoxyalkyl, --S(O)_(m) R¹³,--NHC(═NH)NHR¹³, --C(═NH)NHR¹³, --C(═O)NR¹³ R¹⁴, --NR¹⁴ C(═O)R¹³,═NOR¹⁴, --NR¹⁴ C(═O)OR¹⁴, --OC(═O)NR¹³ R¹⁴, --NR¹³ C(═O)NR¹³ R¹⁴, --NR¹³C(═S)NR¹³ R¹⁴, --NR¹⁴ SO₂ NR¹³ R¹⁴, --NR¹⁴ SO₂ R¹³, --SO₂ NR¹³ R¹⁴, C₁-C₄ alkyl, C₂ -C₄ alkenyl, C₃ -C₁₀ cycloalkyl, C₃ -C₆ cycloalkylmethyl,benzyl, phenethyl, phenoxy, benzyloxy, nitro, C₇ -C₁₀ arylalkyl,hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C₃-C₆ cycloalkoxy, C₁ -C₄ alkyl substituted with --NR¹³ R¹⁴, C₁ -C₄hydroxyalkyl, methylenedioxy, ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄haloalkoxy, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄alkylcarbonyl, C₁ -C₄ alkylcarbonylamino, --OCH₂ CO₂ R¹³,2-(1-morpholino)ethoxy, azido, --C(R¹⁴)═N(OR¹⁴); or

1-3 amino acids, linked together via amide bonds, said amino acid beinglinked via the amine or carboxylate terminus;

a C₅ -C₁ ₄ carbocyclic residue substituted with 0-5 R³² ; or

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R³² ;

R³², when a substituent on carbon, is selected from one or more of thefollowing:

phenethyl, phenoxy, C₃ -C₁₀ cycloalkyl, C₃ -C₆ cycloalkylmethyl, C₇ -C₁₀arylalkyl, hydrazide, oxime, boronic acid, C₂ -C₆ alkoxyalkyl,methylenedioxy, ethylenedioxy, C₁ -C₄ alkylcarbonyloxy, --NHSO₂ R¹⁴,benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO₂ R¹³, hydroxamic acid,--CONR¹³ NR¹³ R¹⁴, cyano, sulfonamide, --CHO, C₃ -C₆ cycloalkoxy, --NR¹³R¹⁴, --C(R¹⁴)═N(OR¹⁴), --NO₂, --OR¹³, --NR⁴⁰ R⁴¹, --SO_(m) R¹³, --SO_(m)NR¹³ R¹⁴, --C(═O)NR¹³ R¹⁴, --OC(═O)NR¹³ R¹⁴, --C(═O)R¹¹, --OC(═O)R¹¹,--OCO₂ R¹³, phenyl, --C(═O)NR¹³ --(C₁ -C₄ alkyl)--NR¹³ R¹⁴, --C(═O)NR⁴⁰R⁴¹, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, C₂ -C₄ haloalkenyl, C₁ -C₄haloalkynyl, or

--C(═O)NR¹³ C(R¹¹)₂ NR¹³ R¹⁴ ;

--C(═O)NR¹³ C(R¹¹)₂ NR¹³ CO₂ R¹³ ;

--C(═O)NR¹³ --(C₁ -C₄ alkyl)--NR¹³ CO₂ R¹³ ;

--C(═O)N(R¹³)--(C₁ -C₄ alkyl)--R¹¹ ; or

--C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ;

--C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ;

--C(═O)--(C₁ -C₄ alkyl)--NR¹³ CO₂ R¹³ ; or

C₁ -C₄ alkoxy substituted with 0-4 groups selected from: R¹¹, C₃ -C₆cycloalkyl, --CO₂ R¹³, --C(═O)NR¹³ R¹⁴, --NR¹³ R¹⁴ or OH;

C₁ -C₄ alkyl substituted with 0-4 groups selected from: R¹¹, ═NR¹⁴,═NNR¹³ C(═O)NR¹³ R14, ═NNR¹³ C(═O)OR¹³, or --NR¹³ R¹⁴ ;

C₂ -C₄ alkenyl substituted with 0-4 R¹¹ ;

C₂ -C₄ alkynyl substituted with 0-4 R¹¹ ;

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur, substituted with0-2 R¹² ;

or R³² may be a 3- or 4-carbon chain attached to adjacent carbons on thering to form a fused 5- or 6-membered ring, said 5- or 6-membered ringbeing optionally substituted on the aliphatic carbons with halogen, C₁-C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, or --NR¹³ R¹⁴ ; or, when R³² isattached to a saturated carbon atom, it may be ═O, ═S, ═NOH; or when R³²attached to sulfur it may be ═O.

R³², when a substituent on nitrogen, is selected from one or more of thefollowing:

phenyl, benzyl, phenethyl, hydroxy, C₁ -C₄ hydroxyalkyl, C₁ -C₄ alkoxy,C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, --CH₂ NR¹³R¹⁴, --NR¹³ R¹⁴, C₂ -C₆ alkoxyalkyl, C₁ -C₄ haloalkyl, C₁ -C₄alkoxycarbonyl, --CO₂ H, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl,--C(R¹⁴)═N(OR¹⁴);

R³⁴ is selected from:

hydrogen;

OR¹³ ;

SR¹³ ;

halogen;

N(R³⁸)(R³⁹)

C₁ -C₆ alkyl substituted with 0-3 R¹¹ ;

C₁ -C₆ alkoxy substituted with 0-3 R¹¹ ;

C₁ -C₆ thioalkyl substituted with 0-3 R¹¹ ;

R³⁵ is selected from:

hydrogen;

OR¹³ ;

SR¹³ ;

halogen;

N(R³⁸)(R³⁹)

C₁ -C₆ alkyl substituted with 0-3 R¹¹ ;

C₁ -C₆ alkoxy substituted with 0-3 R¹¹ ;

C₁ -C₆ thioalkyl substituted with 0-3 R¹¹ ;

R³⁴ and R³⁵ can be taken together to form a ketal ring, a 3- to8-membered carbocyclic ring, or a 5- or 6-membered heterocyclic ringcontaining 1-3 heteroatoms independently selected from the group O, N,or S, said ring substituted with 0-5 R¹¹ ;

R³⁶ is selected from:

H

C₁ -C₆ alkyl substituted with 0-3 R¹¹ ;

--COR³⁷ ;

--NR³⁸ R³⁹ ;

--CN;

--NO₂

R³⁷ is selected from:

hydrogen;

C₁ -C₆ alkyl substituted with 0-3 R¹¹ ;

hydroxyl;

C₁ -C₆ alkoxy substituted with 0-3 R¹¹ ;

--NR³⁸ R³⁹ ;

R³⁸ and R³⁹ are independently selected from:

hydrogen;

C₁ -C₆ alkyl substituted with 0-3 R¹¹ ; or

an amine protecting group;

R⁴⁰ is selected from: H, C₁ -C₃ alkyl;

R⁴¹ is selected from:

--C(═O)NR¹³ R¹⁴ ;

--C(═O)NR¹³ NR¹³ R¹⁴ ;

--C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ;

--C(═O)C(R¹¹)₂ NR¹³ NR¹³ R¹⁴ ;

--C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ;

--C(═O)H;

--C(═O)R¹¹ ;

--C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ;

--C(═O)--(C₁ -C₄ alkyl)--NR¹³ CO₂ R¹³ ;

1-3 amino acids linked together via amide bonds, and linked to the Natom via the carboxylate terminus;

provided that:

R⁴, R^(4A), R⁷ and R^(7A) are not all hydrogen;

when W is --OC(═Z)O--, --SC(═Z)--, --C(═Z)--, --P(═O)(R^(24a))--,--S(═Z')-- or --S(═Z')₂ --, R⁴ and R⁷ are not hydrogen;

when R⁴, R^(4A) are hydrogen, at least one of the following is nothydrogen: R²², R²⁵, and R²⁶.

2! Preferred compounds include those compounds described above wherein:

when W is

--C(═Z)--;

--P(═O)(R^(24a))--;

--S(═Z')--;

--S(═Z')₂ --;

then n is 1 or 2.

3! Preferred compounds include those compounds described above wherein:

R⁴ and R⁷ are independently selected from the following groups:

hydrogen;

C₁ -C₈ alkyl substituted with 0-3 R¹¹ ;

C₂ -C₈ alkenyl substituted with 0-3 R¹¹ ;

C₂ -C₈ alkynyl substituted with 0-3 R¹¹ ;

C₃ -C₈ cycloalkyl substituted with 0-3 R¹¹ ;

C₆ -C₁₀ bicycloalkyl substituted with 0-3 R¹¹ ;

aryl substituted with 0-3 R¹² ;

a C₆ -C₁₄ partially unsaturated carbocyclic residue substituted with 0-3R¹² ;

a 5- to 6-membered heterocyclic ring system containing 1 to 3heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R¹² ;

R²² and R²³ are independently selected from the following:

hydrogen;

C₁ -C₈ alkyl substituted with 0-3 R³¹ ;

C₂ -C₈ alkenyl substituted with 0-3 R³¹ ;

C₂ -C₈ alkynyl substituted with 0-3 R³¹ ;

C₃ -C₈ cycloalkyl substituted with 0-3 R³¹ ;

C₆ -C₁₀ bicycloalkyl substituted with 0-3 R³¹ ;

aryl substituted with 0-5 R³² ;

a C₆ -C₁₄ partially unsaturated carbocyclic residue substituted with 0-3R³² ;

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R³² ;

R²⁵ and R²⁷ are independently selected from the following:

hydrogen;

C₁ -C₈ alkyl substituted with 0-3 R³¹ ;

C₂ -C₈ alkenyl substituted with 0-3 R³¹ ;

C₂ -C₈ alkynyl substituted with 0-3 R³¹ ;

C₃ -C₈ cycloalkyl substituted with 0-3 R³¹ ;

C₆ -C₁₀ bicycloalkyl substituted with 0-3 R³¹ ;

aryl substituted with 0-5 R³² ;

a C₆ -C₁₄ partially unsaturated carbocyclic residue substituted with 0-3R³² ;

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R³².

4! Preferred compounds of this invention are those compounds describedabove with the proviso that when:

W is --C(R²⁵)(R²⁶)C(═Z)C(R²⁷)(R²⁸)--; and

n=0; and

Z is O;

then R²⁵, R²⁶, R²⁷, and R²⁸ are not all H.

5! Preferred compounds of this invention are those compounds describedabove with the proviso that when:

W is --C(R²⁵)(R²⁶)S(═Z')C(R²⁷)(R²⁸)--; and

n=0; and

Z' is O;

then R²⁵, R²⁶, R²⁷, and R²⁸ are not all H.

6! Preferred compounds of this invention are those compounds describedabove with the proviso that when:

W is --C(R²⁵)(R²⁶)S(═Z')₂ C(R²⁷)(R²⁸)--; and

n=0; and

Z' is O or NH;

then R²⁵, R²⁶, R²⁷, and R²⁸ are not all H.

7! Preferred compounds of this invention are those compounds describedabove with the proviso that when:

W is --S(═O)-- or --S(═O)₂ --; and

n=1;

then R⁶ and R^(6a) are not both H.

8! Preferred compounds of this invention are those compounds describedabove with the proviso that when:

W is --C(R²⁵)(R²⁶)C(R³⁴)(R³⁵)C(R²⁷)(R²⁸)--; and

n=0; and

R³⁴ or R³⁵ are N(R³⁸)(R³⁹);

then R²⁵, R²⁶, R²⁷, and R²⁸ are not all H.

9! Preferred compounds of this invention are compounds of the formula(I): ##STR3## or a pharmaceutically acceptable salt or prodrug formthereof wherein: R⁴ and R⁷ are independently selected from the followinggroups:

hydrogen;

C₁ -C₄ alkyl substituted with 0-3 R¹¹ ;

C₃ -C₄ alkenyl substituted with 0-3 R¹¹ ;

C₃ -C₄ alkynyl substituted with 0-3 R¹¹ ;

R^(4A) and R^(7A) are hydrogen;

R⁵ is selected from fluoro, --OR²⁰, --N(R²⁰)₂ ;

R⁶ is independently selected from: hydrogen, fluoro or

--OR²¹ ;

--R⁵ and R⁶ can alternatively join to form an epoxide or aziridine ring;--OCH₂ SCH₂ O--; --OS(═O)O--; --OC(═O)O--; --OCH₂ O--; --OC(═S)O--;--OC(═O)C(═O)O--; --OC(CH₃)₂ O--; --OC(OCH₃)(CH₂ CH₂ CH₃)O--; or anygroup that, when administered to a mammalian subject, cleaves to form afree dihydroxyl;

R^(5a) is selected from hydrogen or fluoro;

R^(6a) is selected from: hydrogen or fluoro;

R⁵ and R^(5a) can alternatively join to form ═O, ═S, or a ketal ring;

R⁶ and R^(6a) can alternatively join to form ═O, ═S, or a ketal ring;

R²⁰ and R²¹ are independently selected from:

hydrogen;

C₁ -C₆ alkylcarbonyl;

C₁ -C₆ alkoxycarbonyl;

benzoyl; or

any group that, when administered to a mammalian subject, cleaves toform a free hydroxyl;

R¹¹ is selected from one or more of the following:

H, keto, halogen, cyano, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, --CO₂ R¹³,--OC(═O)R¹³, --OR¹³, C₂ -C₄ alkoxyalkyl, --S(O)_(m) R¹³, C₁ -C₄ alkyl,C₂ -C₄ alkenyl, C₃ -C₁₀ cycloalkyl;

a C₅ -C₁₄ saturated or partially unsaturated carbocyclic residuesubstituted with 0-3 R¹² ;

aryl(C₁ -C₃ alkyl)-, substituted with 0-2 R¹² ;

aryl substituted with 0-3 R¹² ; or

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R¹² ;

R¹², when a substituent on carbon, is selected from one or more of thefollowing:

phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro,cyano, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, C₇ -C₁₀arylalkyl, C₁ -C₄ alkoxy, 2-(1-morpholino)ethoxy, --CO₂ H, hydroxamicacid, hydrazide, --C(R¹⁴)═N(OR¹⁴), cyano, boronic acid, sulfonamide,formyl, C₃ -C₆ cycloalkoxy, --OR¹³, C₁ -C₄ alkyl substituted with --NR¹³R¹⁴, --NR¹³ R¹⁴, C₂ -C₆ alkoxyalkyl, C₁ -C₄ hydroxyalkyl,methylenedioxy, ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, C₁-C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl, C₁-C₄ alkylcarbonylamino, --S(O)_(m) R¹³, --SO₂ NR¹³ R¹⁴, --NHSO₂ R¹⁴ ; or

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur;

or R¹² may be a 3- or 4-carbon chain attached to adjacent carbons on thering to form a fused 5- or 6-membered ring, said 5- or 6-membered ringbeing optionally substituted on the aliphatic carbons with halogen, C₁-C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, or --NR¹³ R¹⁴ ; or, when R¹² isattached to a saturated carbon atom, it may be ═O or ═S; or when R¹² isattached to sulfur it may be ═O.

R¹², when a substituent on nitrogen, is selected from one or more of thefollowing:

phenyl, benzyl, phenethyl, hydroxy, C₁ -C₄ hydroxyalkyl, C₁ -C₄ alkoxy,C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, --CH₂ NR¹³R¹⁴, --NR¹³ R¹⁴, C₂ -C₆ alkoxyalkyl, C₁ -C₄ haloalkyl, C₁ -C₄alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl, --CO₂ H;

R¹³ is H, C₁ -C₆ alkyl, C₃ -C₆ alkoxyalkyl, C₂ -C₄ alkenyl, phenyl, orbenzyl;

R¹⁴ is OH, H, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, NH₂, C₂ -C₄ alkenyl,phenyl, or benzyl;

R¹³ and R¹⁴ can alternatively join to form --(CH₂)₄ --, --(CH₂)₅ --,--CH₂ CH₂ N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --;

W is selected from:

--N(R²²)C(═Z)N(R²³)--;

--N(R²²)C(═Z)O--;

--C(R²⁵)(R²⁶)C(═Z)C(R²⁷)(R²⁸)--;

--N(R²²)C(═Z)C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)C(═Z)O--;

--N(R²²)C(═O)C(═O)N(R²³)--;

--C(R²⁵)(R²⁶)C(F₂)C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)N(CH₃)(O)C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)N(OR²⁹)C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)C(═Z)S--;

--N(R²²)S(═Z')N(R²³)--;

--N(R²²)S(═Z')₂ N(R²³)--;

--N(R²²)P(═O)(R^(24a))(N(R²³)--;

--C(R²⁵)(R²⁶)S(═Z')C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)S(═Z')₂ C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)P(═O)(R^(24a))C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)S(═Z')N(R²³)--;

--C(R²⁵)(R²⁶)S(═Z')₂ N(R²³)--;

--C(R²⁵)(R²⁶)S(═O)₂ O--;

--C(R²⁵)(R²⁶)P(═O)(R^(24a))N(R²³)--;

--C(R²⁵)(R²⁶)P(═O)(R^(24a))O--;

--C(R²⁵)C(F₂)C(═O)N(R²³)--;

--C(R²⁵)C(F₂)S(═O)₂ N(R²³)--;

--C(R²⁵)(R²⁶)C(R³⁴)(R³⁵)C(R²⁷)(R²⁸)--;

--N═C(R³⁶)N(R²³)--;

--N(R²²)P(R^(24a))N(R²³)--;

--C(═Z)--;

--P(═O)(R^(24a))--;

--S(═Z')--;

--S(═Z')₂ --;

wherein:

Z is O, S, N--CN, N--OH, N--OCH₃ ;

Z' is oxygen:

R²² and R²³ are independently selected from the following:

hydrogen;

C₁ -C₈ alkyl substituted with 0-3 R³¹ ;

C₃ -C₈ alkenyl substituted with 0-3 R³¹ ;

C₃ -C₈ alkynyl substituted with 0-3 R³¹ ;

C₃ -C₆ cycloalkyl substituted with 0-3 R³¹ ;

R^(24a) is selected from --OH, C₁ -C₄ alkoxy, mono- or di-(C₁ -C₆ alkyl)amino;

R²⁵ and R²⁷ are independently selected from the following:

hydrogen;

C₁ -C₈ alkyl substituted with 0-3 R³¹ ;

C₂ -C₈ alkenyl substituted with 0-3 R³¹ ;

C₃ -C₈ alkynyl substituted with 0-3 R³¹ ;

R²⁶ and R²⁸ are hydrogen or halogen;

R²⁹ is selected from:

hydrogen;

C₁ -C₂ alkyl substituted with 0-2 C₁ -C₂ alkoxy;

benzyl substituted with 0-2 halogen or 0-2 C₁ -C₂ alkoxy;

R³¹ is selected from one or more of the following:

keto, halogen, cyano, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, --CO₂ R¹³,--OC(═O)R¹³, --OR¹³, C₂ -C₄ alkoxyalkyl, --S(O)_(m) R¹³, C₁ -C₄ alkyl,C₂ -C₄ alkenyl, C₃ -C₁₀ cycloalkyl, benzyl, phenethyl, phenoxy,benzyloxy, nitro, C₇ -C₁₀ arylalkyl, hydroxamic acid, hydrazide, oxime,boronic acid, sulfonamide, formyl, C₃ -C₆ cycloalkoxy, C₁ -C₄ alkylsubstituted with --NR¹³ R¹⁴, C₁ -C₄ hydroxyalkyl, methylenedioxy,ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, C₁ -C₄alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl, C₁ -C₄alkylcarbonylamino, --OCH₂ CO₂ H, 2-(1-morpholino)ethoxy,--C(R¹⁴)═N(OR¹⁴); or

a C₅ -C₁₄ saturated or partially unsaturated carbocyclic residuesubstituted with 0-3 R³² ;

aryl substituted with 0-3 R³² ; or

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R³² ;

R³², when a substituent on carbon, is selected from one or more of thefollowing:

phenethyl, phenoxy, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, C₇ -C₁₀arylalkyl, hydrazide, oxime, boronic acid, C₂ -C₆ alkoxyalkyl,methylenedioxy, ethylenedioxy, C₁ -C₄ alkylcarbonyloxy, --NHSO₂ R¹⁴,benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO₂ R¹³, hydroxamic acid,--CONR¹³ NR¹³ R¹⁴, cyano, sulfonamide, --CHO, C₃ -C₆ cycloalkoxy, --NR¹³R¹⁴, --C(R¹⁴)═N(OR¹⁴), --NO₂, --OR¹³, --NR⁴⁰ R⁴¹, --SO_(m) R¹³, SO_(m)NR¹³ R¹⁴, --C(═O)NR¹³ R¹⁴, --OC(═O)NR¹³ R¹⁴, --C(═O)R¹¹, --OC(═O)R¹¹,--OCO₂ R¹³, phenyl, --C(═O)NR¹³ -(C₁ -C₄ alkyl)--NR¹³ R¹⁴, --C(═O)NR⁴⁰R⁴¹, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, C₂ -C₄ haloalkenyl, C₂ -C₄haloalkynyl, or

--C(═O)NR¹³ C(R¹¹)₂ NR¹³ R¹⁴ ;

--C(═O)NR¹³ C(R¹¹)₂ NR¹³ CO₂ R¹³ ;

--C(═O)NR¹³ --(C₁ -C₄ alkyl)--NR¹³ CO₂ R¹³ ; or

--C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ;

--C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ;

--C(═O)--(C₁ -C₄ alkyl)--NR¹³ CO₂ R¹³ ; or

C₁ -C₄ alkoxy substituted with 0-3 groups selected from: R¹¹, C₃ -C₆cycloalkyl, --CO₂ R¹³, --C(═O)NR¹³ R¹⁴, --NR¹³ R¹⁴ or OH;

C₁ -C₄ alkyl substituted with 0-3 groups selected from: R¹¹, ═NR¹⁴,═NNR¹³ C(═O)NR¹³ R¹⁴ or -NR¹³ R¹⁴ ; C₂ -C₄ alkenyl substituted with 0-3R¹¹ ; C₂ -C₄ alkynyl substituted with 0-3 R¹¹ ;

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur, substituted with0-2 R¹² ;

or R³² may be a 3- or 4-carbon chain attached to adjacent carbons on thering to form a fused 5- or 6-membered ring, said 5- or 6-membered ringbeing optionally substituted on the aliphatic carbons with halogen, C₁-C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, or --NR¹³ R¹⁴ ; or, when R³² isattached to a saturated carbon atom, it may be ═O or ═S; or when R¹² isattached to sulfur it may be ═O.

R³², when a substituent on nitrogen, is selected from one or more of thefollowing:

phenyl, benzyl, phenethyl, hydroxy, C₁ -C₄ hydroxyalkyl, C₁ -C₄ alkoxy,C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, --CH₂ NR¹³R¹⁴, --NR¹³ R¹⁴, C₂ -C₆ alkoxyalkyl, C₁ -C₄ haloalkyl, C₁ -C₄alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl, --CO₂ H,--C(R¹⁴)═N(OR¹⁴);

R³⁴ is selected from:

hydrogen;

C₁ -C₂ alkyl substituted with 0-1 R¹¹

C₁ -C₂ alkoxy substituted with 0-1 R¹¹

R³⁵ is selected from:

hydrogen

C₁ -C₂ alkyl substituted with 0-1 R¹¹

C₁ -C₂ alkoxy substituted with 0-1 R¹¹

R³⁴ and R³⁵ can be taken together to form a ketal ring, a 3- to8-membered carbocyclic ring, or a 5- or 6-membered heterocyclic ringcontaining 1-3 heteroatoms independently selected from the group O, N,or S;

R³⁶ is selected from:

C₁ -C₂ alkyl substituted with 0-3 R¹¹ ;

COR³⁷ ;

NR³⁸ R³⁹ ;

CN;

R³⁷ is selected from:

hydrogen;

C₁ -C₂ alkyl substituted with 0-1 R¹¹ ;

hydroxyl;

C₁ -C₂ alkoxy substituted with 0-1 R¹¹ ;

NR³⁸ R³⁹ ;

R³⁸ and R³⁹ are independently selected from:

hydrogen;

C₁ -C₂ alkyl substituted with 0-3 R¹¹ ; or

an amine protecting group;

provided that:

R⁴, R^(4A), R⁷, and R^(7A) are not all hydrogen;

when W is --OC(═Z)O--, --C(═Z)--, --P(═O)(R^(24a))--, --S(═Z')-- or--S(═Z')₂ --, R⁴ and R⁷ are not hydrogen;

when R⁴ and R^(4A) are hydrogen, at least one of the following is nothydrogen: R²², R²⁵, and R²⁶.

10! Further preferred compounds of the invention of formula (I) arecompounds of formula (II): ##STR4## or a pharmaceutically acceptablesalt or prodrug form thereof wherein: R⁴ and R⁷ are independentlyselected from the following groups:

hydrogen;

C₁ -C₄ alkyl substituted with 0-3 R¹¹ ;

C₃ -C₄ alkenyl substituted with 0-3 R¹¹ ;

R⁵ is --OR²⁰ ;

R⁶ is hydrogen or --OR²¹ ;

R²⁰ and R²¹ are independently hydrogen or any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl;

R¹¹ is selected from one or more of the following:

H, keto, halogen, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, --OR¹³, C₂ -C₄alkoxyalkyl, C₂ -C₄ alkenyl,

C₃ -C₁₀ cycloalkyl substituted with 0-2 R¹² ;

C₁ -C₄ alkyl substituted with 0-2 R¹² ;

aryl(C₁ -C₃ alkyl)-, substituted with 0-2 R¹² ;

aryl substituted with 0-3 R¹² ; or

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R¹² ;

R¹², when a substituent on carbon, is selected from one or more of thefollowing:

phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, C₁ -C₄ alkyl, C₇-C₁₀ arylalkyl, C₁ -C₄ alkoxy, 2-(1-morpholino)ethoxy, --CO₂ H,hydroxamic acid, hydrazide, --C(R¹⁴)═N(OR¹⁴), cyano, boronic acid,sulfonamide, formyl, C₃ -C₆ cycloalkoxy, --OR¹³, C₁ -C₄ alkylsubstituted with --NR¹³ R¹⁴, --NR¹³ R¹⁴, methylenedioxy, C₁ -C₄haloalkyl, C₁ -C₄ alkylcarbonyl, C₁ -C₄ alkylcarbonylamino,hydroxymethyl; or

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur;

R¹², when a substituent on nitrogen, is selected from benzyl or methyl;

R¹³ is H, C₁ -C₄ alkyl, C₃ -C₆ alkoxyalkyl, C₂ -C₄ alkenyl, or benzyl;

R¹⁴ is OH, H, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, NH₂, C₂ -C₄ alkenyl, orbenzyl;

R¹³ and R¹⁴ can alternatively join to form --(CH₂)₄ --, --(CH₂)₅ --,--CH₂ CH₂ N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --;

W is selected from:

--N(R²²)C(═Z)N(R²³)--;

--N(R²²)C(═Z)O--;

--C(R²⁵)(R²⁶)C(═Z)C(R²⁷)(R²⁸)--;

--N(R²²)C(═Z)C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)C(═Z)O--;

--N(R²²)C(═O)C(═O)N(R²³)--;

--C(R²⁵)(R²⁶)C(═Z)S--;

--N(R²²)S(═Z')N(R²³)--;

--N(R²²)S(═Z')₂ N(R²³)--;

--N(R²²)P(═O)(R^(24a))(N(R²³)--;

--C(R²⁵)(R²⁶)S(═Z')C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)S(═Z')₂ C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)P(═O)(R^(24a))C(R²⁷)(R²⁸)--;

--C(R²⁵)(R²⁶)S(═Z')N(R²³)--;

--C(R²⁵)(R²⁶)S(═Z')₂ N(R²³)--;

--C(R²⁵)C(F₂)C(═O)N(R²³)--;

--C(R²⁵)C(F₂)S(═O)₂ N(R²³)--;

--C(═Z)--;

--P(═O)(R^(24a))--;

--S(═Z')--;

--S(═Z')₂ --;

wherein:

Z is O, S, or N--CN;

Z' is O;

R²² and R²³ are independently selected from the following:

hydrogen;

C₁ -C₈ alkyl substituted with 0-3 R³¹ ;

C₂ -C₆ alkenyl substituted with 0-3 R³¹ ;

C₂ -C₄ alkynyl substituted with 0-3 R³¹ ;

R^(24a) is selected from --OH, C₁ -C₄ alkoxy, mono- or di-(C₁ -C₆ alkyl)amino;

R²⁵ and R²⁷ are independently selected from the following:

hydrogen;

C₁ -C₄ alkyl substituted with 0-3 R³¹ ;

C₂ -C₄ alkenyl substituted with 0-3 R³¹ ;

R²⁶ and R²⁸ are hydrogen or halogen;

R³¹ is selected from one or more of the following:

keto, halogen, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, --OR¹³, C₂ -C₄ alkoxyalkyl-,C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₃ -C₁₀ cycloalkyl, --C(R¹⁴)═N(OR¹⁴),--CO₂ R¹³, --S (O)_(m) R¹³ ;

aryl substituted with 0-5 R³² ; or

a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R³² ;

R³², when a substituent on carbon, is selected from one or more of thefollowing:

phenethyl, phenoxy, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, C₇ -C₁₀arylalkyl, hydrazide, oxime, boronic acid, C₂ -C₆ alkoxyalkyl,methylenedioxy, ethylenedioxy, C₁ -C₄ alkylcarbonyloxy, --NHSO₂ R¹⁴,benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO₂ R¹³, hydroxamic acid,--CONR¹³ NR¹³ R¹⁴, cyano, sulfonamide, --CHO, C₃ -C₆ cycloalkoxy, --NR¹³R¹⁴, --C(R¹⁴)═N(OR¹⁴), --NO₂, --OR¹³, --NR⁴⁰ R⁴¹, --SO_(m) R¹³, --SO_(m)NR¹³ R¹⁴, --C(═O)NR¹³ R¹⁴, --OC(═O)NR¹³ R¹⁴, --C(═O)R¹¹, --OC(═O)R¹¹,--OCO₂ R¹³, phenyl, --C(═O)NR¹³ --(C₁ -C₄ alkyl)--NR¹³ R¹⁴, --C(═O)NR⁴⁰R⁴¹, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, C₂ -C₄ haloalkenyl, C₂ -C₄haloalkynyl, or

--C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ;

--C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ;

--C(═O)--(C₁ -C₄ alkyl)--NR¹³ CO₂ R¹³ ; or

C₁ -C₄ alkoxy substituted with 0-3 groups selected from: R¹¹, C₃ -C₆cycloalkyl, --CO₂ R¹³, --C(═O)NR¹³ R¹⁴, --NR¹³ R¹⁴ or OH;

C₁ -C₄ alkyl substituted with 0-3 groups selected from: R¹¹, ═NR¹⁴,═NNR¹³ C(═O)NR¹³ R¹⁴ or --NR¹³ R¹⁴ ;

C₂ -C₄ alkenyl substituted with 0-3 R¹¹ ;

C₂ -C₄ alkynyl substituted with 0-3 R¹¹ ;

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur, substituted with0-3 R¹² ;

R³², when a substituent on nitrogen, is selected from benzyl or methyl;

R³⁴ is selected from:

hydrogen;

C₁ -C₂ alkyl;

C₁ -C₂ alkoxy;

R³⁵ is selected from:

hydrogen;

C₁ -C₂ alkyl;

C₁ -C₂ alkoxy;

R³⁴ and R³⁵ can be taken together to form a ketal ring, a 3- to8-membered carbocyclic ring, or a 5- or 6-membered heterocyclic ringcontaining 1-2 heteroatoms independently selected from the group O, N,or S;

R³⁶ is selected from: C₁ -C₂ alkyl; COR³⁷ ; NR³⁸ R³⁹ ; CN; CCl₃ ;

R³⁷ is selected from:

hydrogen; C₁ -C₂ alkyl substituted with 0-1 R¹¹ ; hydroxyl; C₁ -C₂alkoxy substituted with 0-1 R¹¹ ; NR³⁸ R³⁹ ;

R³⁸ and R³⁹ are independently selected from:

hydrogen; C₁ -C₂ alkyl substituted with 0-3 R¹¹ ; or

an amine protecting group;

provided that:

R⁴ and R⁷ are not both hydrogen;

when W is --C(═Z)--, --P(═O)(R^(24a))--, --S(═Z')-- or --S(═Z')₂ --, R⁴and R⁷ are not hydrogen;

when R⁴ is hydrogen, at least one of the following is not hydrogen: R²²,R²⁵, R²⁶ and R²⁸.

11! Preferred compounds of the present invention include compounds offormula (II) described above, wherein:

R⁴ and R⁷ are independently selected from the following groups:

hydrogen;

C₁ -C₃ alkyl substituted with 0-1 R¹¹ ;

R²⁰ and R²¹ are independently hydrogen or any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl;

R¹¹ is selected from one or more of the following:

H; halogen; --OR¹³ ;

C₃ -C₁₀ cycloalkyl substituted with 0-2 R¹² ;

C₁ -C₄ alkyl substituted with 0-2 R¹² ;

aryl(C₁ -C₃ alkyl)-, substituted with 0-2 R¹² ;

aryl substituted with 0-2 R¹² ; or

a heterocyclic ring system selected from pyridyl, pyrimidinyl,triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl,oxazolidinyl, said heterocyclic ring system being substituted with 0-2R¹² ;

R¹², when a substituent on carbon, is selected from one or more of thefollowing:

benzyloxy, halogen, methyl, C₁ -C₄ alkoxy, CF₃, 2 -(1-morpholino)ethoxy,--CO₂ H, hydroxamic acid, hydrazide, --C(R¹⁴)═N(OR¹⁴), cyano, boronicacid, sulfonamide, formyl, C₃ -C₆ cycloalkoxy, C₁ -C₄ alkyl substitutedwith --NR¹³ R¹⁴, --NR¹³ R¹⁴, hydroxy, hydroxymethyl; or

R¹², when a substituent on nitrogen, is methyl;

R¹³ is H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, or benzyl;

R¹⁴ is OH, H, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, NH₂, C₂ -C₄ alkenyl, orbenzyl;

R¹³ and R¹⁴ can alternatively join to form --(CH₂)₄ --, --(CH₂)₅ --,--CH₂ CH₂ N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --;

W is selected from:

--N(R²²)C(═Z)N(R²³)--;

--N(R²²)C(═Z)O--;

--C(R²⁵)(R²⁶)C(═Z)C(R²⁷)(R²⁸)--;

--N(R²²)S(═Z')N(R²³)--;

--N(R²²)S(═Z')₂ N(R²³)--;

--C(R²⁵)(R²⁶)C(R³⁴)(R³⁵)C(R²⁷)(R²⁸)--;

--N═C(R³⁶)N(R²³)--;

--C(═Z)--;

Z is O, S, or N--CN;

Z' is O;

R²² and R²³ are independently selected from the following:

hydrogen;

C₁ -C₈ alkyl substituted with 0-3 R³¹ ;

C₂ -C₆ alkenyl substituted with 0-3 R³¹ ;

C₂ -C₄ alkynyl substituted with 0-3 R³¹ ;

R²⁵ and R²⁷ are independently selected from the following:

hydrogen;

C₁ -C₄ alkyl substituted with 0-3 R³¹ ;

C₃ -C₄ alkenyl substituted with 0-3 R³¹ ;

R²⁶ and R²⁸ are hydrogen or halogen;

R³¹ is selected from one or more of the following:

halogen, --OR¹³, C₁ -C₄ alkyl, C₃ -C₁₀ cycloalkyl, --C(R¹⁴)═N(OR¹⁴),--CO₂ R¹³, --S(O)_(m) R¹³ ;

aryl substituted with 0-5 R³² ; or

a heterocyclic ring system chosen from pyridyl, pyrimidinyl, triazinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, saidheterocyclic ring being substituted with 0-2 R³² ;

R³², when a substituent on carbon, is selected from one or more of thefollowing:

benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO₂ R¹³ hydroxamic acid,--CONR¹³ NR¹³ R¹⁴, cyano, boronic acid, --CHO, C₃ -C₆ cycloalkoxy,--NR¹³ R¹⁴, --C(R¹⁴)═N(OR¹⁴), NO₂, --OR¹³, --NR⁴⁰ R⁴¹, --SO_(m) R¹³,--SO_(m) NR¹³ R¹⁴, --C(═O)NR¹³ R¹⁴, --OC(═O)NR¹³ R¹⁴, --C(═O)R¹¹,--OC(═O)R¹¹, --OCO₂ R¹³, phenyl, --C(═O)NR¹³ --(C₁ -C₄ alkyl)--NR¹³ R¹⁴,--C(═O) NR⁴⁰ R⁴¹, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, C₂ -C₄haloalkenyl, C₂ -C₄ haloalkynyl,

--C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ;

--C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ;

--C(═O)--(C₁ -C₄ alkyl)--NR¹³ CO₂ R¹³ ; or

C₁ -C₄ alkoxy substituted with 0-3 groups selected from: R¹¹, C₃ -C₆cycloalkyl, --C(═O)NR¹³ R¹⁴, --NR¹³ R¹⁴ or OH;

C₁ -C₄ alkyl substituted with 0-3 groups selected from: R¹¹, ═NR¹⁴,═NNR¹³ C(═O)NR¹³ R¹⁴ or --NR¹³ R¹⁴ ;

C₂ -C₄ alkenyl substituted with 0-3 R¹¹ ;

C₂ -C₄ alkynyl substituted with 0-3 R¹¹ ;

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur, substituted with0-2 R¹² ;

R³², when a substituent on nitrogen, is methyl;

R³⁴ is selected from:

hydrogen;

C₁ -C₂ alkyl;

C₁ -C₂ alkoxy;

R³⁵ is selected from:

hydrogen;

C₁ -C₂ alkyl;

C₁ -C₂ alkoxy;

R³⁶ is selected from: C₁ -C₂ alkyl; COR³⁷ ; NR³⁸ R³⁹ ; CN; CCl₃ ;

R³⁷ is selected from:

hydrogen;

C₁ -C₂ alkyl substituted with 0-1 R¹¹ ;

hydroxyl;

C₁ -C₂ alkoxy substituted with 0-1 R¹¹ ;

--NR³⁸ R³⁹ ;

R³⁸ and R³⁹ are independently selected from:

hydrogen;

C₁ -C₂ alkyl substituted with 0-3 R¹¹ ; or

an amine protecting group;

provided that:

R⁴ and R⁷ are not both hydrogen;

when W is --C(═Z)--, R⁴ and R⁷ are not hydrogen;

when R⁴ is hydrogen, at least one of the following is not hydrogen: R²²₁ R²⁵, R²⁶ and R²⁸.

12! Preferred compounds of the present invention are compounds offormula (II) described above, wherein:

R⁴ and R⁷ are selected from benzyl, fluorobenzyl, pyrrolylmethyl,methoxybenzyl, isobutyl, nitrobenzyl, aminobenzyl, thienylmethyl,hydroxybenzyl, pyridylmethyl, naphthylmethyl;

R⁵ is --OH;

R⁶ is hydrogen or --OH;

R¹³ is H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, or benzyl;

R¹⁴ is OH, H, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, NH₂, C₂ -C₄ alkenyl, orbenzyl;

R¹³ and R¹⁴ can alternatively join to form --(CH₂)₄ --, --(CH₂)₅ --,--CH₂ CH₂ N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --;

W is selected from:

--N(R²²)C(═O)N(R²³)--;

--N(R²²)C(═N--CN)N(R²³)--;

--N(R²²)S(═O)₂ N(R²³)--;

--C(═O)--;

--N(R²²)C(═S)N(R²³)--; or

--C(═N--CN)--;

R²² and R²³ are independently selected from the following:

hydrogen;

C₁ -C₈ alkyl substituted with 0-2 R³¹ ;

C₂ -C₆ alkenyl substituted with 0-2 R³¹ ;

C₂ -C₄ alkynyl substituted with 0-2 R³¹ ;

R³¹ is selected from one or more of the following:

halogen, --OR¹³, C₁ -C₄ alkyl, C₃ -C₁₀ cycloalkyl, --C(R¹⁴)═N(OR¹⁴),--CO₂ R¹³, --S(O)_(m) R¹³ ;

aryl substituted with 0-5 R³² ; or

a heterocyclic ring system chosen from pyridyl, pyrimidinyl, triazinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl,benzimidazolyl, benzotriazolyl, indazolyl, benzoxazolinyl, benzoxazolyl,said heterocyclic ring being substituted with 0-2 R³² ;

R³², when a substituent on carbon, is selected from one or more of thefollowing:

--CONH₂, --CO₂ H, --CHO, --CH₂ NHOH, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴,hydroxy, hydroxymethyl, --C(R¹⁴)═N(OR¹⁴), halogen, methoxy, methyl,nitro, cyano, allyloxy, --CO₂ CH₃, --NHCHO, --NHCOCH₃, --OCO₂ CH₃,--CH═NCH₂ CH₂ OH, --OCONHCH₂ C₆ H₅, --OCONHCH₃, oxazolidinyl, --C═C--CH₂OH, --COCH₃, hydroxyethyl, C₁ -C₃ alkyl (said alkyl substituted with 0-4halogen, or OH), tetrazolyl, --OCH₂ CONH₂, --CONHNH₂, --CH═NNHCONH₂,--CONHOCH₃, --CH₂ CH(OH)CH₂ OH, adamantamido, hydroxyethoxy,dihydroxyethyl, --C(NH₂)═NH, --CONHCH₃, --B(OH)₂, benzyloxy, --CONHCH₂CH₃, --CON(CH₂ CH₃)₂, methylthio, --SO2CH₃, --NHCONH₂, --NHCONHCH₃,--NHCOCH₂ N(CH₃)₂, --NHCOCH₂ NHCH₃, --NHCOCH₂ NHCO₂ CH₂ C₆ H₅, --NHCOCH₂NH₂, --NHCOCH(CH₃)NHCO₂ CH₂ C₆ H₅, --NHCOCH(CH₂ C₆ H₅)NHCO₂ CH₂ C₆ H₅,--NHCOCH(CH₃)NH₂, --NHCOCH(CH₂ C₆ H₅)NH₂, --CO₂ CH₂ CH₃, --CONHCH₂ CH₂CH₃, --CONHCH(CH₃)₂, --CH₂ --imidazole, --COC(CH₃)₃, --CH(OH)CF₃,--CO--imidazole, --CO--pyrazolyl, oxadiazolidinonyl, --COCF₃, --COCH₂CH₃, --COCH₂ CH₂ CH₃, pyrazolyl, --SO₂ NH₂, --C(CH₂ CH₃)═N(OH) or--C(CF₃)═N(OH), phenyl, acetoxy, hydroxyamino, --N(CH₃)(CHO),cyclopropylmethoxy, --CONR¹³ R¹⁴, --CONHOH,(diethylaminoethyl)aminocarbonyl,(N-ethyl,N-methylaminoethyl)aminocarbonyl,(4-methylpiperazinylethyl)aminocarbonyl,pyrrolidinylethyl)aminocarbonyl, (piperidinylethyl)aminocarbonyl,--NHCOCH₂ NHCH₃, N-(2-(4-morpholino)ethyl)aminocarbonyl,N-(2-(N,N-dimethylamino)ethyl)aminocarbonyl;

R³², when a substituent on nitrogen, is methyl.

13! Also preferred are compounds of the formula: ##STR5## wherein: Z isO, S, or N--CN;

R⁴ and R⁷ are independently selected from: benzyl, fluorobenzyl,pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl, aminobenzyl,thienylmethyl, hydroxybenzyl, pyridylmethyl, naphthylmethyl;

R²² and R²³ are independently selected from the group consisting of:

hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl,i-butyl, CH₂ CH═C(CH₃)₂, pyridinylmethyl, methallyl, n-pentyl, i-pentyl,hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl,cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, naphthylmethyl,methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl,quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl,phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl,methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl,aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl,fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl,fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl,formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H₂ NC(═O))-benzyl,carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, anddimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl,(O-methyl-formaldoxime)benzyl, (CH₃ O₂ CO)-benzyl, (HOCH₂ CH₂N═CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl,N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl,acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronic acid,N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH₃C(═NOH))-benzyl, (H₂ NNHC(═O))-benzyl, (H₂ NC(═O)NHN═CH)-benzyl, (CH₃ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH₃ NHC(═O))-benzyl,N,N-dimethylaminocarbonylbenzyl, (HOCH₂ CH(OH)CH₂₀)-benzyl,hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl,(hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl,(methylthio)benzyl, (methylsulfonyl)benzyl,N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl,glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl,(N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl,(N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH₃ CH₂NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl,N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl,N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl,(hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H₂NSO₂)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H₂NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl,methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl,propionylbenzyl, butyrylbenzyl, (CH₃ CH₂ C(═NOH))-benzyl,(trifluorohydroxyethyl)benzyl, (CF₃ C(═NOH))-benzyl,(N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl,(benzyl-NHC(═O)O)benzyl, (CH₃ NHC(═O)O)benzyl, (NH₂ C(═O)CH₂ O)benzyl,(NH₂ C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl,(imidazolylmethyl)benzyl, ((CH₃)₃ C--C(═O))benzyl,(N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl,(pyrrolidinylethyl)aminocarbonylbenzyl,(piperidinylethyl)aminocarbonylbenzyl, (H₂ NC(═NCH))benzyl, (H₂NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl,indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl,thienylmethyl, furylmethyl.

14! Also preferred are compounds of formula (IIa): ##STR6## wherein R²²and R²³ are independently selected from the group consisting of:

hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl,i-butyl, CH₂ CH═C(CH₃)₂, pyridinylmethyl, methallyl, n-pentyl, i-pentyl,hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl,cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, naphthylmethyl,methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl,quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl,phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl,methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl,aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl,fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl,fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl,formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H₂ NC(═O))-benzyl,carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, anddimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl,(O-methyl-formaldoxime)benzyl, (CH₃ O₂ CO)-benzyl, (HOCH₂ CH₂N═CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl,N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl,acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronic acid,N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH₃C(═NOH))-benzyl, (H₂ NNHC(═O))-benzyl, (H₂ NC(═O)NHN═CH)-benzyl, (CH₃ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH₃ NHC(═O))-benzyl,N,N-dimethylaminocarbonylbenzyl, (HOCH₂ CH(OH)CH₂ O)-benzyl,hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl,(hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl,(methylthio)benzyl, (methylsulfonyl)benzyl,N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl,glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl,(N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl,(N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH₃ CH₂NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl,N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl,N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl,(hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H₂NSO₂)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H₂NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl,methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl,propionylbenzyl, butyrylbenzyl, (CH₃ CH₂ C(═NOH))-benzyl,(trifluorohydroxyethyl)benzyl, (CF₃ C(═NOH))-benzyl,(N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl,(benzyl-NHC(═O)O)benzyl, (CH₃ NHC(═O)O)benzyl, (NH₂ C(═O)CH₂₀)benzyl,(NH₂ C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl,(imidazolylmethyl)benzyl, ((CH₃)₃ C--C(═O))benzyl,(N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl,(pyrrolidinylethyl)aminocarbonylbenzyl,(piperidinylethyl)aminocarbonylbenzyl, (H₂ NC(═NOH))benzyl, (H₂NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl,indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl,thienylmethyl, furylmethyl.

15! Specifically preferred are compounds of formula (IIa): ##STR7##selected from the group consisting of: the compound of formula (IIa)wherein R²² is allyl and R²³ is allyl;

the compound of formula (IIa) wherein R²² is propyl and R²³ is propyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is cyclopropylmethyl;

the compound of formula (IIa) wherein R²² is n-hexyl and R²³ is n-hexyl;

the compound of formula (IIa) wherein R²² is n-butyl and R²³ is n-butyl;

the compound of formula (IIa) wherein R²² is CH₂ CH═C(CH₃)₂ and R²³ isCH₂ CH═C(CH₃)₂ ;

the compound of formula (IIa) wherein R²² is CH₂ CH═C(CH₃)₂ and R²³ isH;

the compound of formula (IIa) wherein R²² is i-pentyl and R²³ isi-pentyl;

the compound of formula (IIa) wherein R²² is 2-methallyl and R²³ is2-methallyl;

the compound of formula (IIa) wherein R²² is n-pentyl and R²³ isn-pentyl;

the compound of formula (IIa) wherein R²² is benzyl and R²³ is benzyl;

the compound of formula (IIa) wherein R²² is i-hexyl and R²³ is i-hexyl;

the compound of formula (IIa) wherein R²² is allyl and R²³ is isoprenyl;

the compound of formula (IIa) wherein R²² is 1-cinnamyl and R²³ is1-cinnamyl;

the compound of formula (IIa) wherein R²² is 4-fluorobenzyl and R²³ is4-fluorobenzyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is benzyl;

the compound of formula (IIa) wherein R²² is allyl and R²³ is benzyl;

the compound of formula (IIa) wherein R²² is CH₂ CH═C(CH₃)₂ and R²³ iscyclopropylmethyl;

the compound of formula (IIa) wherein R²² is 2-naphthylmethyl and R²³ is2-napthylmethyl;

the compound of formula (IIa) wherein R²² is n-butyl and R²³ is benzyl;

the compound of formula (IIa) wherein R²² is allyl and R²³ iscyclopropylmethyl;

the compound of formula (IIa) wherein R²² is n-butyl and R²³ iscyclopropylmethyl;

the compound of formula (IIa) wherein R²² is CH₂ CH═C(CH₃)₂ and R²³ isbenzyl;

the compound of formula (IIa) wherein R²² is benzyl and R²³ is ethyl;

the compound of formula (IIa) wherein R²² is benzyl and R²³ is4-pyridinylmethyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is 4-pyridinylmethyl;

the compound of formula (IIa) wherein R²² is benzyl and R²³ iscyclopentylmethyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is cyclopentylmethyl;

the compound of formula (IIa) wherein R²² is benzyl and R²³ is n-propyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is cinnamyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is 2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is cyclopentylmethyl and R²³is 2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is benzyl and R²³ is2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is 2-pyridinylmethyl;

the compound of formula (IIa) wherein R²² is 3-cyanobenzyl and R²³ is3-cyanobenzyl;

the compound of formula (IIa) wherein R²² is allyl and R²³ is2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is n-propyl and R²³ is2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is n-butyl and R²³ is2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is hydrogen and R²³ is2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is 4-pyridinylmethyl and R²³is 2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is allyl and R²³ iscyclopentylmethyl;

the compound of formula (IIa) wherein R²² is allyl and R²³ is2-quinolinylmethyl;

the compound of formula (IIa) wherein R²² is 3-pyridinylmethyl and R²³is cyclopropylmethyl;

the compound of formula (IIa) wherein R²² is 3-pyridinylmethyl and R²³is 2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is 3-hydroxybenzyl and R²³ is3-hydroxybenzyl;

the compound of formula (IIa) wherein R²² is vinylbenzyl and R²³ isvinylbenzyl;

the compound of formula (IIa) wherein R²² is 3-allyloxybenzyl and R²³ is3-hydroxybenzyl;

the compound of formula (IIa) wherein R²² is 3-pyridinylmethyl and R²³is 3-pyridinylmethyl;

the compound of formula (IIa) wherein R²² is 2-naphthylmethyl and R²³ is4-fluorobenzyl;

the compound of formula (IIa) wherein R²² is 4-hydroxybenzyl and R²³ is4-hydroxybenzyl;

the compound of formula (IIa) wherein R²² is 3-hydroxymethylbenzyl andR²³ is 3-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is 3-carbomethoxybenzyl andR²³ is 3-carbomethoxybenzyl;

the compound of formula (IIa) wherein R²² is 4-hydroxymethylbenzyl andR²³ is 4-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is 3-formylbenzyl and R²³ is3-formylbenzyl;

the compound of formula (IIa) wherein R²² is 4-cyanobenzyl and R²³ is4-cyanobenzyl;

the compound of formula (IIa) wherein R²² is 4-formylbenzyl and R²³ is4-formylbenzyl;

the compound of formula (IIa) wherein R²² is 4-hydroxybenzyl and R²³ is2-propyl;

the compound of formula (IIa) wherein R²² is 3-hydroxybenzyl and R²³ is2-propyl;

the compound of formula (IIa) wherein R²² is 3-carboxybenzyl and R²³ is3-carboxybenzyl;

the compound of formula (IIa) wherein R²² is 3-formaldoximebenzyl andR²³ is 3-formaldoximebenzyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is 3-hydroxybenzyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is 4-hydroxybenzyl;

the compound of formula (IIa) wherein R²² is cyclobutylmethyl and R²³ iscyclobutylmethyl;

the compound of formula (IIa) wherein R²² is cyclopentylmethyl and R²³is cyclopentylmethyl;

the compound of formula (IIa) wherein R²² is n-butyl and R²³ is CH₂CH═C(CH₃)₂ ;

the compound of formula (IIa) wherein R²² is n-butyl and R²³ iscyclopentylmethyl;

the compound of formula (IIa) wherein R²² is benzyl and R²³ is H;

the compound of formula (IIa) wherein R²² is 3-fluorobenzyl and R²³ is3-fluorobenzyl;

the compound of formula (IIa) wherein R²² is 3-methoxybenzyl and R²³ is3-methoxybenzyl;

the compound of formula (IIa) wherein R²² is 3,4-difluorobenzyl and R²³is 3,4-difluorobenzyl;

the compound of formula (IIa) wherein R²² is 4-methylbenzyl and R²³ is4-methylbenzyl;

the compound of formula (IIa) wherein R²² is 4-chlorobenzyl and R²³ is4-chlorobenzyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is 4-fluorobenzyl;

the compound of formula (IIa) wherein R²² is 3-chlorobenzyl and R²³ is3-chlorobenzyl;

the compound of formula (IIa) wherein R²² is 3-nitrobenzyl and R²³ is3-nitrobenzyl;

the compound of formula (IIa) wherein R²² is 3-methylbenzyl and R²³ is3-methylbenzyl;

the compound of formula (IIa) wherein R²² is 3-bromobenzyl and R²³ is3-bromobenzyl;

the compound of formula (IIa) wherein R²² is 4-fluorobenzyl and R²³ isH;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is 3-chlorobenzyl;

the compound of formula (IIa) wherein R²² is 3-minobenzyl and R²³ is3-aminobenzyl;

the compound of formula (IIa) wherein R²² is 4-minobenzyl and R²³ is4-aminobenzyl;

the compound of formula (IIa) wherein R²² is 3-nitrobenzyl and R²³ is H;

the compound of formula (IIa) wherein R²² is 3-(NHCHO)benzyl and R²³ is3-(NHCHO)benzyl;

the compound of formula (IIa) wherein R²² is 3-(NHCOCH₃)benzyl and R²³is 3-(NHCOCH₃)benzyl;

the compound of formula (IIa) wherein R²² is 3,4-dihydroxybenzyl and R²³is 3,4-dihydroxybenzyl;

the compound of formula (IIa) wherein R²² is 3-formaldoximebenzyl andR²³ is 3-(N-hydroxy)aminomethylbenzyl;

the compound of formula (IIa) wherein R²² is3-(N-hydroxy)aminomethylbenzyl and R²³ is3-(N-hydroxy)aminomethylbenzyl;

the compound of formula (IIa) wherein R²² is 3-(CH₃ OC(═O)O--)benzyl andR²³ is 3-(CH₃ OC(═O)O--)benzyl;

the compound of formula (IIa) wherein R²² is 3-(1-hydroxyethyl)benzyland R²³ is 3-(1-hydroxyethyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-(HOCH₂ CH₂ N═CH)benzyland R²³ is 3-(HOCH₂ CH₂ N═CH)benzyl;

the compound of formula (IIa) wherein R²² is 3-(HOCH₂ CH₂ N═CH)benzyland R²³ is 3-(2-oxazolidinyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-(C₆ H5CH₂ NHC(═O)O)benzyland R²³ is 3-(C₆ H₅ CH₂ NHC(═O)O)benzyl;

the compound of formula (IIa) wherein R²² is 3-(CH₃ NHC(═O)O)benzyl andR²³ is 3-(CH₃ NHC(═O)O)benzyl;

the compound of formula (IIa) wherein R²² is 3-(HOCH₂ CC)benzyl and R²³is 3-bromobenzyl;

the compound of formula (IIa) wherein R²² is 3-acetylbenzyl and R²³ is3-bromobenzyl;

the compound of formula (IIa) wherein R²² is 3-acetylbenzyl and R²³ is3-acetylbenzyl;

the compound of formula (IIa) wherein R²² is 3-(CH₃ C(═NOH))benzyl andR²³ is 3-(CH₃ C(═NOH))benzyl;

the compound of formula (IIa) wherein R²² is 3-(1-hydroxyethyl)benzyland R²³ is 3-bromobenzyl;

the compound of formula (IIa) wherein R²² is 3-(chloromethyl)benzyl andR²³ is 3-(chloromethyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-(5-tetrazolyl)benzyl andR²³ is cyclopropylmethyl;

the compound of formula (IIa) wherein R²² is 3-cyanobenzyl and R²³ is3-formylbenzyl;

the compound of formula (IIa) wherein R²² is 4-acetoxybenzyl and R²³ is4-hydroxybenzyl;

the compound of formula (IIa) wherein R²² is 3-aminocarbonylbenzyl andR²³ is 3-aminocarbonylbenzyl;

the compound of formula (IIa) wherein R²² is 3-(H₂ NCOCH₂ O)benzyl andR²³ is 3-(H₂ NCOCH₂ O)benzyl;

the compound of formula (IIa) wherein R²² is 3-hydroxybenzyl and R²³ isH;

the compound of formula (IIa) wherein R²² is 3-methylbenzyl and R²³ is3-hydroxybenzyl;

the compound of formula (IIa) wherein R²² is 2-naphthylmethyl and R²³ is3-hydroxybenzyl;

the compound of formula (IIa) wherein R²² is 3-(H₂ NNHC(═O))-benzyl andR²³ is 3-(H₂ NNHC(═O))-benzyl;

the compound of formula (IIa) wherein R²² is 4-(H₂ NNHC(═O))-benzyl andR²³ is 4-(H₂ NNHC(═O))-benzyl;

the compound of formula (IIa) wherein R²² is 4-hydroxymethylbenzyl andR²³ is 3-hydroxybenzyl;

the compound of formula (IIa) wherein R²² is 3-(H₂ NC(═O)NHN═CH)-benzyland R²³ is 3-(H₂ NC(═O)NHN═CH)-benzyl;

the compound of formula (IIa) wherein R²² is 3-(N-methoxy)aminocarbonyl!-benzyl and R²³ is 3-(N-methoxy)aminocarbonyl!-benzyl;

the compound of formula (IIa) wherein R²² is 4-(N-methoxy)aminocarbonyl!-benzyl and R²³ is 4-(N-methoxy)aminocarbonyl!-benzyl;

the compound of formula (IIa) wherein R²² is 3-(HOCH₂ CH(OH)CH₂ O)benzyland R²³ is 3-(HOCH₂ CH(OH)CH₂ O)benzyl;

the compound of formula (IIa) wherein R²² is 3-(2-hydroxyethoxy)benzyland R²³ is 3-(2-hydroxyethoxy)benzyl;

the compound of formula (IIa) wherein R²² is3-(1,2-dihydroxyethyl)benzyl and R²³ is 4-(1,2-dihydroxyethyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-aminocarbonylbenzyl andR²³ is 3-(H₂ NC(═NH))benzyl;

the compound of formula (IIa) wherein R²² is 4-hydroxybenzyl and R²³ is3-formyl-4-hydroxybenzyl;

the compound of formula (IIa) wherein R²² is 3-carbomethoxybenzyl andR²³ is 3-(N-methylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is3-(N-methylaminocarbonyl)benzyl and R²³ is3-(N-methylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is benzyl and R²³ is3-hydroxybenzyl;

the compound of formula (IIa) wherein R²² is 2-naphthylmethyl and R²³ is4-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is3-(1,2-dihydroxyethyl)benzyl and R²³ is 3-(1,2-dihydroxyethyl)benzyl;

the compound of formula (IIa) wherein R²² is4-(1,2-dihydroxyethyl)benzyl and R²³ is 4-(1,2-dihydroxyethyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-hydroxymethylbenzyl andR²³ is 3-(N-methylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is 4-hydroxymethylbenzyl andR²³ is hydrogen;

the compound of formula (IIa) wherein R²² is 3-(boronic acid)benzyl andR²³ is 3-(boronic acid)benzyl;

the compound of formula (IIa) wherein R²² is 3-nitrobenzyl and R²³ is3-benzyloxybenzyl;

the compound of formula (IIa) wherein R²² is 3-aminobenzyl and R²³ is3-hydroxybenzyl;

the compound of formula (IIa) wherein R²² is3-(N-ethylaminocarbonyl)benzyl and R²³ is3-(N-ethylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-carbomethoxybenzyl andR²³ is 3-(N,N-diethylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-carbomethoxybenzyl andR²³ is 3-(N-ethylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is 6-hydroxy-1-hexyl and R²³is hydrogen;

the compound of formula (IIa) wherein R²² is 6-hydroxy-1-hexyl and R²³is 6-hydroxy-1-hexyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is 6-hydroxy-1-hexyl;

the compound of formula (IIa) wherein R²² is 5-carboxy-1-pentyl and R²³is 5-carboxy-1-pentyl;

the compound of formula (IIa) wherein R²² is 3-iodobenzyl and R²³ is3-iodobenzyl;

the compound of formula (IIa) wherein R²² is benzyl and R²³ is2-(hydroxymethyl)-cyclopropylmethyl;

the compound of formula (IIa) wherein R²² is 3-(thiomethyl)benzyl andR²³ is 3-(thiomethyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-(methylsulfonyl)benzyland R²³ is 3-(methylsulfonyl)benzyl;

the compound of formula (IIa) wherein R²² is 6-hexenyl and R²³ is6-hexenyl;

the compound of formula (IIa) wherein R²² is 6-bromo-5-hydroxy-1-hexyland R²³ is 6-bromo-5-hydroxy-1-hexyl;

the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is 5-hydroxy-1-pentyl;

the compound of formula (IIa) wherein R²² is 3-aminobenzyl and R²³ is4-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is 3-(H₂ NC(═O)NH)benzyl andR²³ is 3-(H₂ NC(═O)NH)benzyl;

the compound of formula (IIa) wherein R²² is 3-(N-methylamino)benzyl andR²³ is 3-(N-methylamino)benzyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is 3-aminobenzyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is 3-nitrobenzyl;

the compound of formula (IIa) wherein R²² is 3-(N,N-dimethylamino)benzyland R²³ is 3-(N,N-dimethylamino)benzyl;

the compound of formula (IIa) wherein R²² is 3-nitrobenzyl and R²³ is4-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is 3-aminobenzyl and R²³ is3-(CH₃ NHC(═O)NH)benzyl;

the compound of formula (IIa) wherein R²² is 3-(CH₃ NHC(═O)NH)benzyl andR²³ is 3-(CH₃ NHC(═O)NH)benzyl;

the compound of formula (IIa) wherein R²² is 3-(N-methylamino)benzyl andR²³ is 4-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is3-((N,N-dimethylaminoglycyl)amino)benzyl and R²³ is3-((N,N-dimethylaminoglycyl)amino)benzyl;

the compound of formula (IIa) wherein R²² is3-((N-methylaminoglycyl)amino)benzyl and R²³ is3-((N-methylaminoglycyl)amino)benzyl;

the compound of formula (IIa) wherein R²² is3-((N,N-dimethylaminoglycyl)amino)benzyl and R²³ is4-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is3-((N-phenylmethoxycarbonylaminoglycyl)amino)benzyl and R²³ is3-((N-phenylmethoxycarbonylaminoglycyl)amino)benzyl;

the compound of formula (IIa) wherein R²² is 3-(glycylamino)benzyl andR²³ is 3-(glycylamino)benzyl;

the compound of formula (IIa) wherein R²² is 3-(glycylamino)benzyl andR²³ is 4-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is3-((N-phenylmethoxycarbonylamino-L-alanyl)amino)benzyl and R²³ is3-((N-phenylmethoxycarbonylamino-L-alanyl)amino)benzyl;

the compound of formula (IIa) wherein R²² is3-((N-phenylmethoxycarbonylamino-L-phenylalanyl)amino)benzyl and R²³ is3-((N-phenylmethoxycarbonylamino-L-phenylalanyl)amino)benzyl;

the compound of formula (IIa) wherein R²² is 3-(L-alanyl)amino)benzyland R²³ is 3-(L-alanyl)amino)benzyl;

the compound of formula (IIa) wherein R²² is3-(L-phenylalanyl)amino)benzyl and R²³ is3-(L-phenylalanyl)amino)benzyl;

the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is hydrogen;

the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is 2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is benzyl;

the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is 4-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is 6-hydroxy-1-hexyl and R²³is 2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is 3-hydroxybenzyl;

the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is (5-methylsulfonyl)-1-pentyl;

the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is 5-(CH₃ S(O))-1-pentyl;

the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is cyclopropylmethyl;

the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is 5-methoxy-1-pentyl;

the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is 3-cyanobenzyl;

the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is 3-carboethoxybenzyl;

the compound of formula (IIa) wherein R²² is 4-hydroxy-1-hexyl and R²³is 4-hydroxy-1-hexyl;

the compound of formula (IIa) wherein R²² is 4-hydroxy-1-hexyl and R²³is 2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is 4-oxime-1-hexyl and R²³ is4-oxime-1-hexyl;

the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is 3-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is 6-amino-1-hexyl and R²³ is4-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is3-(N,N-diethylaminocarbonyl)benzyl and R²³ is3-(N,N-diethylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-carbomethoxybenzyl andR²³ is 3-(N,N-diethylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-carbomethoxybenzyl andR²³ is 3-(N-ethylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-hydroxymethylbenzyl andR²³ is hydrogen;

the compound of formula (IIa) wherein R²² is 3-hydroxymethylbenzyl andR²³ is 3-(N,N-diethylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-hydroxymethylbenzyl andR²³ is 3-(N-ethylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is3-(N-propylaminocarbonyl)benzyl and R²³ is3-(N-propylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-(HO₂ C)benzyl and R²³ is3-(N-isopropylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-(HO₂ C)benzyl and R²³ is3-(N-propylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-(HO₂ C)benzyl and R²³ isbenzyl;

the compound of formula (IIa) wherein R²² is 3-(HO₂ C)benzyl and R²³ iscyclopropylmethyl;

the compound of formula (IIa) wherein R²² is 4-hydroxymethylbenzyl andR²³ is 3-(HO₂ C)benzyl;

the compound of formula (IIa) wherein R²² is 3-hydroxymethylbenzyl andR²³ is 3-pyridinylmethyl;

the compound of formula (IIa) wherein R²² is 4-hydroxymethylbenzyl andR²³ is 3-aminocarbonylbenzyl;

the compound of formula (IIa) wherein R²² is 3-aminobenzyl and R²³ is2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is 3-aminocarbonylbenzyl;

the compound of formula (IIa) wherein R²² is 3-aminocarbonylbenzyl andR²³ is hydrogen;

the compound of formula (IIa) wherein R²² is 3-hydroxymethylbenzyl andR²³ is 3-(N-ethylaminocarbonyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-hydroxymethylbenzyl andR²³ is 3-(N-methylamino)benzyl;

the compound of formula (IIa) wherein R²² is 3-(N-methylamino)benzyl andR²³ is 2-naphthylmethyl;

the compound of formula (IIa) wherein R²² is 4-formylbenzyl and R²³ is4-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is 3-(1-hydroxy-1-ethyl)benzyland R²³ is 3-(1-hydroxyethyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-pyridinylmethyl and R²³is 4-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is3-(N-imidazolylmethyl)benzyl and R²³ is 3-(N-imidazolylmethyl)benzyl;

the compound of formula (IIa) wherein R²² is3-(2,2-dimethyl-1-propionyl)benzyl and R²³ is3-(2,2-dimethyl-1-propionyl)benzyl;

the compound of formula (IIa) wherein R²² is3-(2,2,2-trifluoro-1-hydroxyethyl)benzyl and R²³ is3-(2,2,2-trifluoro-1-hydroxyethyl)benzyl;

the compound of formula (IIa) wherein R²² is3-(2-imidazolyl-C(═O))benzyl and R²³ is 3-(2-imidazolyl-C(═O))benzyl;

the compound of formula (IIa) wherein R²² is3-(3-hydroxy-1-propyn-1-yl)benzyl and R²³ is3-(3-hydroxy-1-propyn-1-yl)benzyl;

the compound of formula (IIa) wherein R²² is3-(2,2,2-trifluoroacetyl)benzyl and R²³ is3-(2,2,2-trifluoroacetyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-propionylbenzyl and R²³is 3-propionylbenzyl;

the compound of formula (IIa) wherein R²² is 3-(4-pyrazolyl)benzyl andR²³ is 3-(4-pyrazolyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-(CH₃ CH₂ C(═N--OH))benzyland R²³ is 3-(CH₃ CH₂ C(═N--OH))benzyl;

the compound of formula (IIa) wherein R²² is 3-sulfonamidobenzyl and R²³is 3-sulfonamidobenzyl;

the compound of formula (IIa) wherein R²² is 3-(CF₃ CH₂ C(═N--OH))benzyland R²³ is 3-(CF₃ CH₂ C(═N--OH))benzyl;

the compound of formula (IIa) wherein R²² is 4-fluoromethylbenzyl andR²³ is 4-fluoromethylbenzyl;

the compound of formula (IIa) wherein R²² is 4-(1-hydroxyethyl)benzyland R²³ is 4-(1-hydroxyethyl)benzyl;

the compound of formula (IIa) wherein R²² is3-(5-methyl-1,2,3-oxadiazolyl)benzyl and R²³ is3-(5-methyl-1,2,3-oxadiazolyl)benzyl;

the compound of formula (IIa) wherein R²² is 3-(H₂ NC(═NOH)benzyl andR²³ is 3-(H₂ NC(═NOH)benzyl;

the compound of formula (IIa) wherein R²² is 3-(H₂NC(═NOH)-4-fluorobenzyl and R²³ is 3-(H₂ NC(═NOH)-4-fluorobenzyl;

the compound of formula (IIa) wherein R²² is 5-benzotriazolylmethyl andR²³ is 5-benzotriazolylmethyl;

the compound of formula (IIa) wherein R²² is 5-benzimidazolylmethyl andR²³ is 5-benzimidazolylmethyl;

the compound of formula (IIa) wherein R²² is 5-benzimidazolylmethyl andR²³ is 5-benzimidazolylmethyl;

the compound of formula (IIa) wherein R²² is 5-benzotriazolylmethyl andR²³ is 4-hydroxymethylbenzyl;

the compound of formula (IIa) wherein R²² is 5-benzotriazolylmethyl andR²³ is 3-(3-pyrazolyl)benzyl;

the compound of formula (IIa) wherein R²² is 5-indazolylmethyl and R²³is 5-indazolylmethyl;

the compound of formula (IIa) wherein R²² is 3-chloro-5-indazolylmethyland R²³ is 3-chloro-5-indazolylmethyl;

the compound of formula (IIa) wherein R²² is3-methylamino-5-indazolylmethyl and R²³ is3-methylamino-5-indazolylmethyl;

the compound of formula (IIa) wherein R²² is3-ethylamino-5-indazolylmethyl and R²³ is3-ethylamino-5-indazolylmethyl;

the compound of formula (IIa) wherein R²² is 6-indazolylmethyl and R²³is 6-indazolylmethyl;

the compound of formula (IIa) wherein R²² is3-amino-5-benzisoxazolylmethyl and R²³ is3-amino-5-benzisoxazolylmethyl;

the compound of formula (IIa) wherein wherein R²² is5-(2-amino)benzoxazolyl and R²³ is 5-(2-amino)benzoxazolyl.

16! Also preferred are compounds of formula (IIaa): ##STR8## or apharmaceutically acceptable salt or prodrug form thereof wherein: R⁴ andR⁷ are independently selected from: benzyl, fluorobenzyl,pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl, aminobenzyl,hydroxybenzyl, thienylmethyl, pyridylmethyl, naphthylmethyl;

R²² and R²³ are independently selected from:

hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl,i-butyl, CH₂ CH═C(CH₃)₂, pyridinylmethyl, methallyl, n-pentyl, i-pentyl,hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl,cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyl-oxazolinylmethyl,naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl,pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl,benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl,methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl,hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl,allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl,chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl,cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl,(H₂ NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl,tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl,(O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH₃ O₂CO)-benzyl, (HOCH₂ CH₂ N═CH)-benzyl, N-benzylaminocarbonylbenzyl,N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl,acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronicacid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH₃C(═NOH))-benzyl, (H₂ NNHC(═O))-benzyl, (H₂ NC(═O)NHN═CH)-benzyl, (CH₃ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH₃ NHC(═O))-benzyl,N,N-dimethylaminocarbonylbenzyl, (HOCH₂ CH(OH)CH₂ O)-benzyl,hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl,(hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl,(methylthio)benzyl, (methylsulfonyl)benzyl,N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl,glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl,(N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl,(N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH₃ CH₂NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl,N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl,N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl,(hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H₂NSO₂)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H₂NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl,methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl,propionylbenzyl, butyrylbenzyl, (CH₃ CH₂ C(═NOH))-benzyl,(trifluorohydroxyethyl)benzyl, (CF₃ C(═NOH))-benzyl,(N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl,(benzyl-NHC(═O)O)benzyl, (CH₃ NHC(═O)O)benzyl, (NH₂ C(═O)CH₂ O)benzyl,(NH₂ C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl,(imidazolylmethyl)benzyl, ((CH₃)₃ C--C(═O))benzyl,(N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl,(pyrrolidinylethyl)aminocarbonylbenzyl,(piperidinylethyl)aminocarbonylbenzyl, (H₂ NC(═NOH))benzyl, (H₂NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl,indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl,thienylmethyl, furylmethyl.

17! Specifically preferred are compounds of formula (IIaa): ##STR9##selected from the group consisting of: the compound of formula (IIaa)wherein R⁴ and R⁷ are isobutyl, R²² and R²³ are cyclopropylmethyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are isobutyl, R²² andR²³ are allyl;

the compound of formula (IIaa) wherein R⁴ is 4-nitrobenzyl, R⁷ is2-nitrobenzyl, R²² and R²³ are cyclopropylmethyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-nitrobenzyl, R²²and R²³ are cyclopropylmethyl;

the compound of formula (IIaa) wherein R⁴ is 4-nitrobenzyl, R⁷ is2-nitrobenzyl, R²² and R²³ are n-butyl;

the compound of formula (IIaa) wherein R⁴ is 4-aminobenzyl, R⁷ is2-aminobenzyl, R²² and R²³ are cyclopropylmethyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²²and R²³ are 3-hydroxybenzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²²and R²³ are cyclopropylmethyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²²and R²³ are 4-hydroxymethylbenzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²²and R²³ are 3-aminocarbonylbenzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²²and R²³ are 3-acetylbenzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²²and R²³ are 3-butyrylbenzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²²and R²³ are 3-hydroxymethylbenzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²²and R²³ are 3-(CH₃ C(═N--OH)benzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 3-methoxybenzyl,R²² and R²³ are benzyl.

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²²and R²³ are 3-(H₂ NC(═NOH)benzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²²and R²³ are 3-(H₂ NC(═NOH)-4-fluorobenzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 3-methoxybenzyl,R²² and R²³ are cyclopropylmethyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 3-methoxybenzyl,R²² and R²³ are 4-hydroxymethylbenzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 3-methoxybenzyl,R²² and R²³ are 3-methoxybenzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 3-hydroxybenzyl,R²² and R²³ are 3-hydroxybenzyl.

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-methoxybenzyl,R²² and R²³ are cyclopropylmethyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-methoxybenzyl,R²² and R²³ are benzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-methoxybenzyl,R²² and R²³ are 2-naphthylmethyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-methoxybenzyl,R²² and R²³ are 4-hydroxymethylbenzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-hydroxybenzyl,R²² and R²³ are benzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-methoxybenzyl,R²² and R²³ are allyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are4-(2-hydroxyethoxy)benzyl, R²² and R²³ are benzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are4-(2-morpholinylethoxy)benzyl, R²² and R²³ are benzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 3-(H₂ NC(═O)CH₂O)benzyl, R²² and R²³ are n-butyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 3,4-difluorobenzyl,R²² and R²³ are 3-hydroxymethylbenzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 3,4-difluorobenzyl,R²² and R²³ are 4-hydroxymethylbenzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 3,4-difluorobenzyl,R²² and R²³ are 3-(H₂ NC(═O))benzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 3,4-difluorobenzyl,R²² and R²³ are 3-(H₂ NC(═NOH))benzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 2-naphthylmethyl,R²² and R²³ are benzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 2-naphthylmethyl,R²² and R²³ are cyclopropylmethyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 2-thienylmethyl,R²² and R²³ are cyclopropylmethyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 2-thienylmethyl,R²² and R²³ are 3-(H₂ NC(═NOH))benzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-methylthiobenzyl,R²² and R²³ are benzyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are isopropyl, R²² andR²³ are n-hexyl;

the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-pyridylmethyl,R²² and R²³ are benzyl.

18! Also preferred in the present invention are compounds of formula(IIb): ##STR10## or a pharmaceutically acceptable salt or prodrug formthereof wherein: R²² and R²³ are independently selected from the groupconsisting of:

hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl,i-butyl, CH₂ CH═C(CH₃)₂, pyridinylmethyl, methallyl, n-pentyl, i-pentyl,hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl,cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, naphthylmethyl,methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl,quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl,phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl,methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl,aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl,fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl,fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl,formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H₂ NC(═O))-benzyl,carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, anddimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl,(O-methyl-formaldoxime)benzyl, (CH₃ O₂ CO)-benzyl, (HOCH₂ CH₂N═CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl,N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl,acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronic acid,N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH₃C(═NOH))-benzyl, (H₂ NNHC(═O))-benzyl, (H₂ NC(═O)NHN═CH)-benzyl, (CH₃ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH₃ NHC(═O))-benzyl,N,N-dimethylaminocarbonylbenzyl, (HOCH₂ CH(OH)CH₂ O)-benzyl,hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl,(hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl,(methylthio)benzyl, (methylsulfonyl)benzyl,N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl,glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl,(N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl,(N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH₃ CH₂NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl,N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl,N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl,(hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H₂NSO₂)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H₂NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, nmethanesulfonylpentyl,methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl,propionylbenzyl, butyrylbenzyl, (CH₃ CH₂ C(═NOH))-benzyl,(trifluorohydroxyethyl)benzyl, (CF₃ C(═NOH))-benzyl,(N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl,(benzyl-NHC(═O)O)benzyl, (CH₃ NHC(═O)O)benzyl, (NH₂ C(═O)CH₂ O)benzyl,(NH₂ C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl,(imidazolylmethyl)benzyl, ((CH₃)₃ C--C(═O))benzyl,(N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl,(pyrrolidinylethyl)aminocarbonylbenzyl,(piperidinylethyl)aminocarbonylbenzyl, (H₂ NC(═NOH))benzyl, (H₂NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl,indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl,thienylmethyl, furylmethyl.

19! Specifically preferred are compounds of formula (IIb): ##STR11##selected from the group consisting of: the compound of formula (IIb)wherein R²² is 4-hydroxybenzyl and R²³ is 4-hydroxybenzyl;

the compound of formula (IIb) wherein R²² is cyclopentylmethyl and R²³is cyclopentylmethyl;

the compound of formula (IIb) wherein R²² is n-butyl and R²³ is n-butyl;

the compound of formula (IIb) wherein R²² is 3-hydroxybenzyl and R²³ is3-hydroxybenzyl;

the compound of formula (IIb) wherein R²² is 3-aminobenzyl and R²³ is3-aminobenzyl;

the compound of formula (IIb) wherein R²² is cyclohexylmethyl and R²³ iscyclohexylmethyl;

the compound of formula (IIb) wherein R²² is cyclobutylmethyl and R²³ iscyclobutylmethyl;

the compound of formula (IIb) wherein R²² is 3-hydroxymethylbenzyl andR²³ is 3-hydroxymethylbenzyl;

the compound of formula (IIb) wherein R²² is 3-formylbenzyl and R²³ is3-formylbenzyl;

the compound of formula (IIb) wherein R²² is 3-formaldoximebenzyl andR²³ is 3-formaldoximebenzyl.

20! Also preferred in the present invention are compounds of the formula(Ibb): ##STR12## or a pharmaceutically acceptable salt or prodrug formthereof wherein: R²² and R²³ are independently selected from the groupconsisting of:

hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl,i-butyl, CH₂ CH═C(CH₃)₂, pyridinylmethyl, methallyl, n-pentyl, i-pentyl,hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl,cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyl-oxazolinylmethyl,naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl,pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl,benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl,methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl,hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl,allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl,chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl,cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl,(H₂ NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl,tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl,(O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH₃ O₂CO)-benzyl, (HOCH₂ CH₂ N═CH)-benzyl, N-benzylaminocarbonylbenzyl,N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl,acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronicacid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH₃C(═NOH))-benzyl, (H₂ NNHC(═O))-benzyl, (H₂ NC(═O)NHN═CH)-benzyl, (CH₃ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH₃ NHC(═O))-benzyl,N,N-dimethylaminocarbonylbenzyl, (HOCH₂ CH(OH)CH₂ O)-benzyl,hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl,(hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl,(methylthio)benzyl, (methylsulfonyl)benzyl,N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl,glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl,(N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl,(N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH₃ CH₂NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl,N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl,N,N-diisopropyl-aminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl,(hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H₂NSO₂)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H₂NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl,methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl,propionylbenzyl, butyrylbenzyl, (CH₃ CH₂ C(═NOH))-benzyl,(trifluorohydroxyethyl)benzyl, (CF₃ C(═NOH))-benzyl,(N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl,(benzyl-NHC(═O)O)benzyl, (CH₃ NHC(═O)O)benzyl, (NH₂ C(═O)CH₂ O)benzyl,(NH₂ C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl,(imidazolylmethyl)benzyl, ((CH₃)₃ C--C(═O))benzyl,(N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl,(pyrrolidinylethyl)aminocarbonylbenzyl,(piperidinylethyl)aminocarbonylbenzyl, (H₂ NC(═NOH))benzyl, (H₂NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl,indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl,thienylmethyl, furylmethyl.

21! Specifically preferred are compounds of formula (Ibb): ##STR13##selected from the group consisting of: the compound of formula (Ibb)wherein R²² is benzyl and R²³ is hydrogen;

the compound of formula (Ibb) wherein R²² is cyclopropylmethyl and R²³is cyclopropylmethyl;

the compound of formula (Ibb) wherein R²² is benzyl and R²³ is benzyl;

the compound of formula (Ibb) wherein R²² is 3-hydroxybenzyl and R²³ is3-hydroxybenzyl.

the compound of formula (Ibb) wherein R²² is 3-hydroxymethylbenzyl andR²³ is 3-hydroxymethylbenzyl;

the compound of formula (Ibb) wherein R²² is 4-hydroxybenzyl and R²³ is4-hydroxybenzyl;

the compound of formula (Ibb) wherein R²² is 3-methoxybenzyl and R²³ is3-methoxybenzyl;

the compound of formula (Ibb) wherein R²² is 3-(H₂ NC(═NOH))benzyl andR²³ is 4-hydroxymethylbenzyl;

the compound of formula (Ibb) wherein R²² is 3-(H₂ NC(═NOH))benzyl andR²³ is 3-(H₂ NC(═NOH))benzyl;

the compound of formula (Ibb) wherein R²² is 3-(H₂NC(═NOH))-4-fluorobenzyl and R²³ is 3-(H₂ NC(═NOH))-4-fluorobenzyl;

22! Also preferred in the present invention are compounds of the formula(Ic): ##STR14## or a pharmaceutically acceptable salt or prodrug formthereof wherein: R³³ is OH, halogen, H, N₃ or can alternatively be takentogether with R²³ to form a direct bond;

wherein R²² and R²³ are independently selected from the group consistingof:

hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl,i-butyl, CH₂ CH═C(CH₃)₂, pyridinylmethyl, methallyl, n-pentyl, i-pentyl,hexyl, benzyl, isoprenyl, propargyl, methoxyethyl, cyclohexylmethyl,dimethyl-butyl, ethoxyethyl, naphthylmethyl, methyloxazolinylmethyl,vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl,chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl,cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl,hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl,cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl,chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl,bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl,nitrobenzyl, (H₂ NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl,tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl,(O-benzyl-formaldoxime)benzyl, (O-nmethyl-formaldoxime)benzyl, (CH₃ O₂CO)-benzyl, (HOCH₂ CH₂ N═CH)-benzyl, N-benzylaminocarbonylbenzyl,N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl,acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronicacid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH₃C(═NOH))-benzyl, (H₂ NNHC(═O))-benzyl, (H₂ NC(═O)NHN═CH)-benzyl, (CH₃ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH₃ NHC(═O))-benzyl,N,N-dimethylaminocarbonylbenzyl, (HOCH₂ CH(OH)CH₂ O)-benzyl,hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl,(hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl,(methylthio)benzyl, (methylsulfonyl)benzyl,N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl,glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl,(N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl,(N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH₃ CH₂NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl,N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl,N,N-diisopropyl-aminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl,(hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H₂NSO₂)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H₂NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl,methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl,propionylbenzyl, butyrylbenzyl, (CH₃ CH₂ C(═NOH))-benzyl,(trifluorohydroxyethyl)benzyl, (CF₃ C(═NOH))-benzyl,(N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl,(benzyl-NHC(═O)O)benzyl, (CH₃ NHC(═O)O)benzyl, (NH₂ C(═O)CH₂ O)benzyl,(NH₂ C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl,(imidazolylmethyl)benzyl, ((CH₃)₃ C--C(═O))benzyl,(N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl,(pyrrolidinylethyl)aminocarbonylbenzyl,(piperidinylethyl)aminocarbonylbenzyl, (H₂ NC(═NOH))benzyl, (H₂NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl,indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl,thienylmethyl, furylmethyl.

23! Specifically preferred are compounds of formula (Ic): ##STR15##selected from the group consisting of: the compound of formula (Ic)wherein R²² is 3-hydroxybenzyl, R²³ is 3-hydroxybenzyl and R³³ ishydrogen;

the compound of formula (Ic) wherein R²² is 3-acetylbenzyl, R²³ is3-acetylbenzyl and R³³ is hydrogen;

the compound of formula (Ic) wherein R²² is 3-hydroxymethylbenzyl, R²³is 3-hydroxymethylbenzyl and R³³ is hydrogen.

the compound of formula (Ic) wherein R²² is 3-(H₂ NC(═O))benzyl, R²³ is3-(H₂ NC(═O))benzyl and R³³ is hydrogen.

the compound of formula (Ic) wherein R²² is 3-(H₂ NC(═NOH))benzyl, R²³is 3-(H₂ NC(═NOH))benzyl and R³³ is hydrogen.

the compound of formula (Ic) wherein R²² is 3-(H₂NC(═O))-4-fluorobenzyl, R²³ is 3-(H₂ NC(═O))-4-fluorobenzyl and R³³ ishydrogen.

the compound of formula (Ic) wherein R²² is 3-(H₂NC(═NOH))-4-fluorobenzyl, R²³ is 3-(H₂ NC(═NOH))-4-fluorobenzyl and R³³is hydrogen.

24! Also preferred are compounds of formula (IId): ##STR16## or apharmaceutically acceptable salt or prodrug form thereof wherein: R²²and R²³ are independently selected from the group consisting of:

hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl,i-butyl, CH₂ CH═C(CH₃)₂, pyridinylmethyl, methallyl, n-pentyl, i-pentyl,hexyl, benzyl, isoprenyl, propargyl, methoxyethyl, cyclohexylmethyl,dimethyl-butyl, ethoxyethyl, naphthylmethyl, methyloxazolinylmethyl,vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl,chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl,cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl,hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl,cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl,chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl,bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl,nitrobenzyl, (H₂ NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl,tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl,(O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH₃ O₂CO)-benzyl, (HOCH₂ CH₂ N═CH)-benzyl, N-benzylaminocarbonylbenzyl,N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl,acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethylboronicacid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH₃C(═NOH))-benzyl, (H₂ NNHC(═O))-benzyl, (H₂ NC(═O)NHN═CH)-benzyl, (CH₃ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH₃ NHC(═O))-benzyl,N,N-dimethylaminocarbonylbenzyl, (HOCH₂ CH(OH)CH₂ O)-benzyl,hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl,(hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl,(methylthio)benzyl, (methylsulfonyl)benzyl,N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl,glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl,(N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl,(N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH₃ CH₂NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl,N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl,N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl,(hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolidinonyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H₂NSO₂)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H₂NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl,methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl,propionylbenzyl, butyrylbenzyl, (CH₃ CH₂ C(═NOH))-benzyl,(trifluorohydroxyethyl)benzyl, (CF₃ C(═NOH))-benzyl,(N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl,(benzyl-NHC(═O)O)benzyl, (CH₃ NHC(═O)O)benzyl, (NH₂ C(═O)CH₂ O)benzyl,(NH₂ C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl,(imidazolylmethyl)benzyl, ((CH₃)₃ C--C(═O))benzyl,(N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl, (pyrrolidinylethyl)aminocarbonylbenzyl, (piperidinylethyl)aminocarbonylbenzyl, (H₂NC(═NOH))benzyl, (H₂ NC(═NOH))fluorobenzyl, benzimidazolylmethyl,benzotriazolylmethyl, indazolylmethyl, benzoxazolinylmethyl,benzisoxazolylmethyl, thienylmethyl, furylmethyl.

25! Specifically preferred are compounds of formula (IId): ##STR17##selected from the group consisting of: the compound of formula (IId)wherein R²² is 4-hydroxymethylbenzyl and R²³ is 4-hydroxymethylbenzyl;

the compound of formula (IId) wherein R²² is 3-hydroxybenzyl and R²³ is3-hydroxybenzyl;

the compound of formula (IId) wherein R²² is cyclopropylmethyl and R²³is cyclopropylmethyl;

the compound of formula (IId) wherein R²² is 2-naphthylmethyl and R²³ is2-naphthylmethyl;

the compound of formula (IId) wherein R²² is 4-hydroxybenzyl and R²³ is4-hydroxybenzyl;

the compound of formula (IId) wherein R²² is 3-aminobenzyl and R²³ is3-aminobenzyl;

the compound of formula (IId) wherein R²² is 3-hydroxymethylbenzyl andR²³ is 3-hydroxymethylbenzyl;

the compound of formula (IId) wherein R²² is 3-(Me₂ NCH₂ C(═O)NH)-benzyland R²³ is 3-(Me₂ NCH₂ C(═O)NH)-benzyl;

the compound of formula (IId) wherein R²² is 3-formaldoximebenzyl andR²³ is 3-formaldoximebenzyl;

the compound of formula (IId) wherein R²² is 3-(CH₃ C(═NOH))-benzyl andR²³ is 3-(CH₃ C(═NOH))-benzyl;

the compound of formula (IId) wherein R²² is 3-(2-amino-4-thienyl)benzyland R²³ is 3-(2-amino-4-thienyl)benzyl;

the compound of formula (IId) wherein R²² is 5-hydroxypentyl and R²³ is5-hydroxypentyl;

the compound of formula (IId) wherein R²² is 6-hydroxypentyl and R²³ is6-hydroxypentyl;

the compound of formula (IId) wherein R²² is 5-hydroxypentyl and R²³ is2-naphthylmethyl;

the compound of formula (IId) wherein R²² is 5-hydroxypentyl and R²³ is4-hydroxymethylbenzyl;

the compound of formula (IId) wherein R²² is 5-hydroxypentyl and R²³ is3-hydroxymethylbenzyl.

52! Also included in the present invention are compounds, or apharmaceutically acceptable salt form thereof, selected from thefollowing formulae: ##STR18## wherein: R⁴ and R⁷ are independentlyselected from the following groups:

hydrogen;

C₁ -C₃ alkyl substituted with 0-1 R¹¹ ;

R⁵ is --OR²⁰ ;

R⁶ is hydrogen or --OR²¹ ;

R²⁰ and R²¹ are independently hydrogen or any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl;

R¹¹ is selected from one or more of the following:

H; halogen; --OR¹³ ;

C₃ -C₁₀ cycloalkyl substituted with 0-2 R¹² ;

C₁ -C₄ alkyl substituted with 0-2 R¹² ;

aryl(C₁ -C₃ alkyl) substituted with 0-2 R¹² ;

aryl substituted with 0-2 R¹² ; or

a heterocyclic ring system selected from pyridyl, pyrimidinyl,triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl,oxazolidinyl, said heterocyclic ring system being substituted with 0-2R¹² ;

R¹², when a substituent on carbon, is selected from one or more of thefollowing:

benzyloxy, halogen, methyl, C₁ -C₄ alkoxy, CF₃, 2-(1-morpholino)ethoxy,--CO₂ H, hydroxamic acid, hydrazide, --C(R¹⁴)═N(OR¹⁴), cyano, boronicacid, sulfonamide, formyl, C₃ -C₆ cycloalkoxy, C₁ -C₄ alkyl substitutedwith --NR¹³ R¹⁴, --NR¹³ R¹⁴, hydroxy, hydroxymethyl; or

R¹², when a substituent on nitrogen, is methyl;

R¹³ is H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, or benzyl;

R¹⁴ is OH, H, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, NH₂, C₂ -C₄ alkenyl, orbenzyl;

R¹³ and R¹⁴ can alternatively join to form --(CH₂)₄ --, --(CH₂)₅ --,--CH₂ CH₂ N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --;

R¹⁵ is H or CH₃ ;

R²² and R²³ are independently selected from the following:

hydrogen;

C₁ -C₈ alkyl substituted with 0-3 R³¹ ;

C₂ -C₆ alkenyl substituted with 0-3 R³¹ ;

C₂ -C₄ alkynyl substituted with 0-3 R³¹ ;

R³¹ is selected from one or more of the following:

halogen, --OR¹³, C₁ -C₄ alkyl, C₃ -C₁₀ cycloalkyl, --C(R¹⁴)═N(OR¹⁴),--CO₂ R¹³, --S(O)_(m) R¹³ ;

aryl substituted with 0-5 R³² ; or

a heterocyclic ring system chosen from pyridyl, pyrimidinyl, triazinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, saidheterocyclic ring being substituted with 0-2 R³² ;

R³², when a substituent on carbon, is selected from one or more of thefollowing:

benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO₂ R¹³, hydroxamic acid,--CONR¹³ NR¹³ R.sup.₁₄, cyano, boronic acid, sulfonamide, --CHO, C₃ -C₆cycloalkoxy, --NR¹³ R¹⁴, --C(R¹⁴)═N(OR¹⁴) NO₂, --OR¹³, --NR⁴⁰ R⁴¹,--SO_(m) R¹³, --SO_(m) NR¹³ R¹⁴, --C(═O)NR¹³ R¹⁴, --OC(═O)NR¹³ R¹⁴,--C(═C)R¹¹, --OC(═O)R¹¹, --OCO₂ R¹³, phenyl, --C(═O)NR¹³ --(C₁ -C₄alkyl)--NR¹³ R¹⁴, --C(═O)NR⁴⁰ R⁴¹, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy,C₂ -C₄ haloalkenyl, C₁ -C₄ haloalkynyl, --C(═O)NNR¹³ R¹⁴ ;--C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ NR¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³CO₂ R¹³ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ; --C(═O)--(C₁ -C₄alkyl)--NR¹³ CO₂ R¹³ ; or

C₁ -C₄ alkoxy substituted with 0-3 groups selected from: R¹¹, C₃ -C₆cycloalkyl, --C(═O)NR¹³ R¹⁴, --NR¹³ R¹⁴ or OH;

C₁ -C₄ alkyl substituted with 0-3 groups selected from: R¹¹, ═NR¹⁴,═NNR¹³ C(═O)NR¹³ R¹⁴ or --NR¹³ R¹⁴ ;

C₂ -C₄ alkenyl substituted with 0-3 R¹¹ ;

C₂ -C₄ alkynyl substituted with 0-3 R¹¹ ;

a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur substituted with0-2 R¹² ;

R³², when a substituent on nitrogen, is methyl;

m is 0, 1, or 2;

R³⁶ is selected from: C₁ -C₂ alkyl; COR³⁷ ; NR³⁸ R³⁹ ; CN; CCl₃ ;

R³⁷ is selected from:

hydrogen;

C₁ -C₂ alkyl substituted with 0-1 R¹¹ ;

hydroxyl;

C₁ -C₂ alkoxy substituted with 0-1 R¹¹ ;

--NR³⁸ R³⁹ ;

R³⁸ and R³⁹ are independently selected from:

hydrogen;

C₁ -C₂ alkyl substituted with 0-3 R¹¹ ; or

an amine protecting group;

R⁴⁰ is selected from: H, C₁ -C₃ alkyl;

R⁴¹ is selected from:

--C(═O)NR¹³ R¹⁴ ;

--C(═O)NR¹³ NR¹⁴ ;

--C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ;

--C(═O)C(R¹¹)₂ NR¹³ NR¹⁴ ;

--C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ;

--C(═O)H;

--C(═O)R¹¹ ;

--C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ;

--C(═O)--(C₁ -C₄ alkyl)--NR¹³ CO₂ R¹³ ; 1-3 amino acids linked togethervia amide bonds, and linked to the N atom via the carboxylate terminus.

53! Another aspect of the invention is a process for preparing cycliccompounds of formula (I): ##STR19## wherein: W is selected from:

--N(R²²)C(═O)N(R²³)--;

--N(R²²)C(═S)N(R²³)--;

--N(R²²)S(═O)₂ N(R²³)--;

R²² and R²³ are as defined above, provided that at least one of R²² orR²³ must be H;

R⁴, R^(4A), R⁷, R^(7A), R^(5a), and R^(6a) are as defined above;

n is 0, 1, or 2;

R²⁰ and R²¹ are as defined above and may in addition be selected from ahydroxyl protecting group;

said process comprising the step of reacting an acyclic diamine compoundof the formula (III): ##STR20## with a suitable cyclizing reagent in asuitable solvent, said solvent optionally comprising a base, thereby toform a compound of formula (I).

For compounds of formula (I) wherein W is --N(R²²)C(═O)N(R²³)--, thesuitable cyclizing reagent may be selected from, but is not limited to,phenyl chloroformate, phenyl tetrazoylformate, urea, phosgene,triphosgene, oxalyl chloride, N,N'-disuccinimidyl carbonate,1,1'-carbonyldiimidazole, trichloromethyl chloroformate, and2(S),3-pyridinediyl thiocarbonate. A preferred cyclizing reagent is1,1'-carbonyl diimidazole.

For compounds of formula (I) wherein W is --N(R²²)C(═S)N(R²³)--, thesuitable cyclizing reagent may be selected from, but is not limited to,1,1'-thiocarbonyl diimidazole or carbon disulfide. Preferably, thecyclizing reagent is 1,1'-thiocarbonyldiimidazole.

For compounds of formula (I) wherein W is --N(R²²)S(═O)₂ N(R²³)--, thesuitable cyclizing reagent may be selected from, but is not limited to,sulfamide.

A base may optionally be included in the above-described method in orderto account for the lability of the R²⁰ and R²¹ hydroxyl protectinggroups to the cyclization conditions. The base may be selected fromorganic bases which include, but are not limited to, pyridine,diisopropylethylamine, and triethylamine. The base may alternatively beselected from inorganic bases which include but are not limited tosodium hydroxide.

The above-described reaction is carried out in a suitable solvent, forexample, in an organic solvent or in a biphasic suspension of water andan organic solvent. Suitable solvents include chlorinated organicsolvents which include, but are not limited to, chloroform, methylenechloride, tetrachloroethane, butyl chloride and dichloroethane. Apreferrable chlorinated organic solvent is chloroform. Thenon-chlorinated organic solvents useful in the method of the inventioninclude, but are not limited to tetrahydrofuran, N,N-dimethylformamideand toluene. A preferrable non-chlorinated organic solvent is toluene.

The reaction can be conducted at a temperature of from about 0° C. toabout the boiling point of the solvent selected, 153° C. in the case ofN,N-dimethylformamide. Preferably, the temperature of the reaction isabout 0° C. to about room temperature.

The time required for completion of the reaction can range from about 1hour to about 5 days, depending on the combination of cyclizing reagent,solvent, base and stereoisomer of compound (III) selected. The reactioncan be run under nitrogen or other inert atmosphere, provided that anychanges in concentration and integrity of the reagents due todecomposition are compensated for.

As used herein, the term "hydroxyl protecting group" means any groupknown in the art of organic synthesis for the protection of hydroxylgroups. Such protecting groups include those listed in Greene and Wuts,"Protective Groups in Organic Synthesis", John Wiley & Sons, New York(1991), the disclosure of which is hereby incorporated by reference. Thehydroxyl protecting groups are base-stable and can include, but are notlimited to acyl types, aromatic carbamate types and alkyl types.Exemplary are methyl, methoxymethyl, methylthiomethyl, benzyloxymethyl,t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl,t-butyl, triphenylmethyl, trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, pivaloate orN-phenylcarbamate.

55! Another aspect of the invention is a process for preparing cycliccompounds of formula (Icc): ##STR21## wherein: R⁴, R⁷, R²⁰, R²², R²³ areas defined above, and R³³ is hydrogen or halogen;

with the proviso that neither R²² or R²³ are hydrogen.

said process comprising the step of reacting a cyclic urea of formula(IIaaa) ##STR22## with a reagent capable of converting the free hydroxyin the compound of formula (IIaaa) to a suitable leaving group and, atthe same time, providing in situ a suitable nucleohilic species to bringabout a ring contraction, in a suitable solvent, thereby to form acompound of formula (Icc).

The above reagent may be selected from, but is not limited to,2-acetoxyisobutyryl bromide, DAST, or a combination oftriphenylphosphine/DEAD/chloroacetic acid. The preferred reagent whenR²⁰ and R³³ are hydrogen is 2-acetoxyisobutyryl bromide.

The above-described reaction is carried out in a suitable solvent, forexample, in an organic solvent. Suitable solvents include chlorinatedorganic solvents which include, but are not limited to, chloroform,methylene chloride, tetrachloroethane, butyl chloride anddichloroethane. A preferrable chlorinated organic solvent isdichloromethane. The non-chlorinated organic solvents useful in themethod of the invention include, but are not limited to tetrahydrofuran,diethyl ether and toluene. A preferrable non-chlorinated organic solventis tetrahydrofuran.

The reaction can be conducted at a temperature of from about 0° C. to50° C. Preferably, the temperature of the reaction is about 0° C. toabout room temperature.

The time required for completion of the reaction can range from about 5min to about 24 hr, depending on the combination of solvent, andsubstitution on compound (IIaaa) selected. The reaction can be run undernitrogen or other inert atmosphere, provided that any changes inconcentration and integrity of the reagents due to decomposition arecompensated for.

For compounds of Formula (1cc) wherein R³³ is hydrogen, a second stepcomprising reacting a compound of formula (1cc), wherein R³³ is bromo,with a suitable dehalogenation reagent is required. Suitabledehalogenation reagents may be selected from but are not limited totri-n-butyltin hydride or zinc dust. Preferred reagents aretri-n-butyltin hydride or zinc. Suitable solvents in the case oftri-n-butyltin hydride include toluene, tetrahydrofuran or benzene, withthe preferred solvent being toluene. The reaction may be carried out ata temperature of from about 50° C. to about 120° C. Preferably, thetemperature of the reactions is from 80° C. to 120° C. The time requiredfor completion of the reaction is from about 30 min to about 6 hr. Inthe case where the reagent used is zinc dust, then the preferred solventis glacial acetic acid, the prefferred temperature is room temperature,and the time required for completion of reaction is from about 1 hr toabout 48 hr.

Hereby incorporated herein by reference is copending commonly assignedU.S. Patent Application of Jadhav and Emmett (attorney docket numberDM-6627) filed Mar. 30, 1993.

In the present invention it has been discovered that the compounds offormula (I) above are useful as inhibitors of HIV protease and similarretroviral proteases, and for the inhibition of HIV and the treatment ofHIV infection and similar retrovirus infections.

The present invention also provides methods for the treatment of HIVinfection by administering to a host infected with HIV apharmaceutically or therapeutically effective or acceptable amount of acompound of formula (I) as described above. By therapeutically effectiveamount, it is meant an amount of a compound of the present inventioneffective to inhibit HIV infection or treat the symptoms of HIVinfection in a host.

The compounds of formula (I) of the present invention are also usefulfor the inhibition of HIV in an ex vivo sample containing HIV orexpected to be exposed to HIV. Thus, the compounds of the presentinvention may be used to inhibit HIV present in a body fluid sample (forexample, a serum or semen sample) which contains or is suspected tocontain or be exposed to HIV.

The compounds provided by this invention are also useful as standard orreference compounds for use in tests or assays for determining theability of an agent to inhibit viral replication and/or HIV protease,for example in a pharmaceutical research program. Thus, the compounds ofthe present invention may be used as a control or reference compound insuch assays and as a quality control standard. The compounds of thepresent invention may be provided in a commercial kit or container foruse as such standard or reference compound.

Since the compounds of the present invention exhibit specificity for HIVprotease, the compounds of the present invention may also be useful asdiagnostic reagents in diagnostic assays for the detection of HIVprotease. Thus, inhibition of the protease activity in an assay (such asthe assays described herein) by a compound of the present inventionwould be indicative of the presence of HIV protease and HIV virus.

The compounds herein described may have asymmetric centers. All chiral,diastereomeric, and racemic forms are included in the present invention.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. It will beappreciated that certain compounds of the present invention contain anasymmetrically substituted carbon atom, and may be isolated in opticallyactive or racemic forms. It is well known in the art how to prepareoptically active forms, such as by resolution of racemic forms or bysynthesis, from optically active starting materials. Also, it isrealized that cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms. All chiral, diastereomeric,racemic forms and all geometric isomeric forms of a structure areintended, unless the specific stereochemistry or isomer form isspecifically indicated.

When any variable (for example, R¹ through R⁴¹, R^(4A) and R^(7A), m, n,W, Z, etc.) occurs more than one time in any constituent or in formula(I) or (II), or any other formula herein, its definition on eachoccurrence is independent of its definition at every other occurrence.Thus, for example, if a group is shown to be substituted with 0-3 R¹¹,then said group may optionally be substituted with up to three R¹¹ andR¹¹ at each occurrence is selected independently from the defined listof possible R¹¹. Also, for example, in --N(R²⁰)₂, each of the R²⁰substituents may be independently selected from the list of possible R²⁰groups defined. Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.Similarly, by way of example, for the group --C(R¹¹)₂ --, each of thetwo R¹¹ substituents on C is independently selected from the definedlist of possible R¹¹.

As used herein, "alkyl" is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms; "haloalkyl" is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morehalogen (for example --C_(v) F_(w) where v=1 to 3 and w=1 to (2v+1));"alkoxy" represents an alkyl group of indicated number of carbon atomsattached through an oxygen bridge; "cycloalkyl" is intended to includesaturated ring groups, including mono-,bi- or poly-cyclic ring systems,such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl and cyclooctyl; and "biycloalkyl" is intended to includesaturated bicyclic ring groups such as 3.3.0!bicyclooctane,4.3.0!bicyclononane, 4.4.0!bicyclodecane (decalin), 2.2.2!bicyclooctane,and so forth. "Alkenyl" is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or more unsaturatedcarbon-carbon bonds which may occur in any stable point along the chain,such as ethenyl, propenyl, and the like; and "alkynyl" is intended toinclude hydrocarbon chains of either a straight or branchedconfiguration and one or more triple carbon--carbon bonds which mayoccur in any stable point along the chain, such as ethynyl, propynyl andthe like.

The terms "-(alkyl)-", "-(alkyenyl)-", "-(phenyl)-", and the like, referto alkyl, alkenyl, and phenyl groups, respectively, which are connectedby two bonds to the rest of the structure of Formula I. Such groups mayalternatively and equivalently be denoted as "alkylene", "alkenylene","phenylene", and the like, respectively.

"Alkylcarbonyl" is intended to include an alkyl group of an indicatednumber of carbon atoms attached through a carbonyl group to the residueof the compound at the designated location. "Alkylcarbonylamino" isintended to include an alkyl group of an indicated number of carbonatoms attached through a carbonyl group to an amino bridge, where thebridge is attached to the residue of the compound at the designatedlocation. "Alkylcarbonyloxy" is intended to include an alkyl group of anindicated number of carbon atoms attached to a carbonyl group, where thecarbonyl group is attached through an oxygen atom to the residue of thecompound at the designated location.

"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, andiodo; and "counterion" is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate, and thelike.

As used herein, "aryl" or "aromatic residue" is intended to mean phenylor naphthyl; the term "arylalkyl" represents an aryl group attachedthrough an alkyl bridge. By way of examples: the term "C₇ -C₁₀arylalkyl" is intended to refer to an aryl group attached through a C₁-C₄ alkyl bridge to the residue of the indicated compound; the term "(C₁-C₃ alkyl)aryl" is intended to refer to a C₁ -C₃ alkyl group which isattached through an aryl ring to the residue of the indicated compound;the term "aryl(C₁ -C₃ alkyl)" is intended to refer to an aryl groupattached through a C₁ -C₃ alkyl group to the residue of the indicatedcompound.

As used herein, "carbocycle" or "carbocyclic residue" is intended tomean any stable 3- to 7-membered monocyclic or bicyclic or 7- to14-membered bicyclic or tricyclic or an up to 26-membered polycycliccarbon ring, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocyles include, but are not limited to,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl,indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclicheterocyclic ring which is either saturated or unsaturated, and whichconsists of carbon atoms and from 1 to 4 heteroatoms independentlyselected from the group consisting of N, O and S and wherein thenitrogen and sulfur heteroatoms may optionally be oxidized, and thenitrogen may optionally be quaternized, and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The heterocyclic ring may be attached to its pendant groupat any heteroatom or carbon atom which results in a stable structure.The heterocyclic rings described herein may be substituted on carbon oron a nitrogen atom if the resulting compound is stable. Examples of suchheterocycles include, but are not limited to, pyridinyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thiophenyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl,xanthenyl, phenoxathiinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl,pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl,1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl,carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl,phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl,pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl,quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl,benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also includedare fused ring and spiro compounds containing, for example, the aboveheterocycles. Preferred heterocycles include, but are not limited to,pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl,benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl,benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl.

When a bond to a substituent is shown to cross the bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of formula I,then such substituent may be bonded via any atom in such substituent.For example, when the substituent is piperazinyl, piperidinyl, ortetrazolyl, unless specified otherwise, said piperazinyl, piperidinyl,tetrazolyl group may be bonded to the rest of the compound of formula(I) via any atom in such piperazinyl, piperidinyl, tetrazolyl group.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. By stable compound orstable structure it is meant herein a compound that is sufficientlyrobust to survive isolation to a useful degree of purity from a reactionmixture, and formulation into an efficacious therapeutic agent.

The term "substituted", as used herein, means that an one or morehydrogen on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

As used herein, the term "any group that, when administered to amammalian subject, cleaves to form a free hydroxyl, amino or sulfhydryl"means any group bonded to an O, N, or S atom, respectively, which iscleaved from the O, N, or S atom when the compound is administered to amammalian subject to provide a compound having a remaining freehydroxyl, amino, or sulfhydryl group, respectively. Examples of groupsthat, when administered to a mammalian subject, are cleaved to form afree hydroxyl, amino or sulfhydryl, include but are not limited to,phosphate esters, C₁ -C₆ alkyl substituted with 0-3 R¹¹, C₃ -C₆alkoxyalkyl substituted with 0-3 R¹¹, C₁ -C₆ alkylcarbonyl substitutedwith 0-3 R¹¹, C₁ -C₆ alkoxycarbonyl substituted with 0-3 R¹¹, C₁ -C₆alkylaminocarbonyl substituted with 0-3 R¹¹ benzoyl substituted with 0-3R¹², phenoxycarbonyl substituted with 0-3 R¹², phenylaminocarbonylsubstituted with 0-3 R¹², or heteroarylcarbonyl. Examples of groupsthat, when administered to a mammalian subject, are cleaved to form afree hydroxyl, amino or sulfhydryl, may include hydroxy, amine orsulfhydryl protecting groups, respectively.

As used herein, the term "amine protecting group" means any group knownin the art of organic synthesis for the protection of amine groups. Suchamine protecting groups include those listed in Greene and Wuts,"Protective Groups in Organic Synthesis" John Wiley & Sons, New York(1991) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, AcademicPress, New York (1981), the disclosure of which is hereby incorporatedby reference. Any amine protecting group known in the art can be used.Examples of amine protecting groups include, but are not limited to, thefollowing: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, andp-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl(Cbz) and substituted benzyloxycarbonyls,1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl(Fmoc); 3) aliphatic carbamate types such as tertbutyloxycarbonyl (Boc),ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4)cyclic alkyl carbamate types such as cyclopentyloxycarbonyl andadamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl;6) trialkylsilane such as trimethylsilane; and 7) thiol containing typessuch as phenylthiocarbonyl and dithiasuccinoyl.

By a "ketal ring" or "ketal" group is meant any ketal protecting groupwhich can be hydroyzed to form a carbonyl. Such ketal rings or ketalprotecting groups are well known in the art of organic synthesis andtypically include, for example, substituted or unsubstituted carbocyclicdiethers, dithioethers, or mixed ethers. Such ketal protecting groupsinclude those listed in Greene and Wuts, "Protective Groups in OrganicSynthesis" John Wiley & Sons, New York (1991).

The term "amino acid" as used herein means an organic compoundcontaining both a basic amino group and an acidic carboxyl group.Included within this term are natural amino acids, modified and unusualamino acids, as well as amino acids which are known to occurbiologically in free or combined form but usually do not occur inproteins. Included within this term are modified and unusual aminoacids,such as those disclosed in, for example, Roberts and Vellaccio(1983) The Peptides, 5: 342-429, the teaching of which is herebyincorporated by reference. Modified or unusual amino acids which can beused to practice the invention include, but are not limited to, D-aminoacids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid,ornithine, 2,4-diaminobutyric acid, homoarginine, norleucine,N-methylaminobutyric acid, naphthylalanine, phenylglycine,β-phenylproline, tert-leucine, 4-aminocyclohexylalanine,N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine,N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid,6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid,2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylicacid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoicacid.

The term "amino acid residue" as used herein means that portion of anamino acid (as defined herein) that is present in a peptide.

The term "peptide" as used herein means a compound that consists of twoor more amino acids (as defined herein) that are linked by means of apeptide bond. The term "peptide" also includes compounds containing bothpeptide and non-peptide components, such as pseudopeptide or peptidemimetic residues or other non-amino acid components. Such a compoundcontaining both peptide and non-peptide components may also be referredto as a "peptide analog".

The term "peptide bond" means a covalent amide linkage formed by loss ofa molecule of water between the carboxyl group of one amino acid and theamino group of a second amino acid.

As used herein, "pharmaceutically acceptable salts" refer to derivativesof the disclosed compounds wherein the parent compound of formula (I) ismodified by making acid or base salts of the compound of formula (I).Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like.

"Prodrugs" are considered to be any covalently bonded carriers whichrelease the active parent drug according to formula (I) in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of thecompounds of formula (I) are prepared by modifying functional groupspresent in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds of formula (I) wherein hydroxy,amine, or sulfhydryl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, or sulfhydryl group, respectively. Examples of prodrugs include,but are not limited to, acetate, formate, or benzoate derivatives ofalcohol and amine functional groups in the compounds of formula (I);phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters,aminoalkyl esters and carboxyalkyl esters of alcohol and phenolfunctional groups in the compounds of formula (I); and the like.

The pharmaceutically acceptable salts of the compounds of formula (I)include the conventional non-toxic salts or the quaternary ammoniumsalts of the compounds of formula (I) formed, for example, fromnon-toxic inorganic or organic acids. For example, such conventionalnon-toxic salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric andthe like; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the compounds of formula (I) which contain a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, p. 1418, the disclosure of which is herebyincorporated by reference.

As used herein, "W" is not intended to be a symbol for tungsten.

The disclosures of all of the references cited herein are herebyincorporated herein by reference in their entirety.

SYNTHESIS

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include but are not limitedto those methods described below.

The compounds of the present invention may be synthesized using thegeneral synthetic procedures described below. Each of the referencescited below are hereby incorporated herein by reference. All thetemperatures are reported herein in degrees Celsius.

Compounds of the invention wherein:

W is --N(R²²)C(═Z)N(R²³)-- or --N(R²²)C(═O)C(═O)N(R²³)-- or--N(R²²)S(═Z')N(R²³)-- or --N(R²²)S(═Z')₂ N(R²³)-- or--N(R²²)P(═O)(R^(24a))N(R²³)-- or --N(R²²)C(F₂)C(═O)N(R²³)-- or--N(R²²)C(F₂)S(═O)N(R²³)--;

R⁵ is --OR²⁰ or H;

R⁶ is --OR²¹ or H; and

n is 1; can be formed from diamines of formula (III): ##STR23## Thediamines of formula (III) can be synthesized as described in copendingcommonly assigned patent application Jadhav et al. U.S. patentapplication Ser. No. 07/714,042, filed May 31, 1991. Alternative methodswhich can be used to synthesize the compounds of structure (III) aboveare described in European Patent Application Publication Number402646A1, U.S. Pat. No. 4,837,204, and Canadian Patent Application2,026,832.

The compounds of formula (III) can be cyclized to form compounds offormula (IV) under conditions normally used to form cyclic ureas, as isknown to one skilled in the art. Reagents J--(C═Z)--J', where J and J'are leaving groups, are employed, preferably under relatively diluteconditions (for example, less than about 0.1M), to effect ring closureto provide compounds of formula (I). Many examples of J and J' areknown; preferred are carbonyl diimidazole, thiocarbonyldiimidazole,phosgene, thiophosgene, diphenyl carbonate, or diphenyl thiocarbonate.Additionally, for compounds wherein W is --N(R²²)C(═O)C(═O)N(R²³)--,compounds of formula (III) can be reacted with activated derivatives ofoxalic acid, preferably oxalyl chloride, under the above conditions toform the diamide.

For compounds of the invention where R²⁰ or R²¹ is --OH, it isadvantageous to protect the free hydroxyl before cyclization. Protectinggroups used can include any of those listed in Greene and Wuts,Protective Groups in Organic Synthesis, Chapter 2, Wiley, NY (1991). Thepreferred protecting groups are trimethylsilylethoxymethyl (SEM),methoxyethoxymethyl (MEM), or methoxymethyl (MOM).

Cyclization of compounds of formula (III) results in structure (IV)(i.e., structure (I) wherein W is --N(R²²)C(═O)C(═O)N(R²³)-- and n is1). ##STR24##

Another, preferred method to form compounds of formula (IV), in caseswherein R²² and R²³ are linked to their respective nitrogens by a CH₂residue, is to cyclize a compound of structure (III) where R²² and R²³are hydrogen, and to alkylate the nitrogens using a base, a phasetransfer catalyst, and an alkylating agent, using methods well known inthe art. The preferred base is sodium hydride, and the preferredalkylating agents are R²² Y and R²³ Y, wherein Y is a halogen, triflate,or mesylate, preferably a bromide or iodide. Preferred conditions are inpolar aprotic solvents between 0° and 100° C.

Cleavage of protecting groups, if employed, yields structures of formula(I) wherein R⁵ and R⁶ are hydroxyl.

When R⁵ and R⁶ are other than OR²⁰ and OR²¹, some chemical manipulationof functional groups may need to be performed in the preparation of thecompounds of formula (III) or (IV), as is appreciated by one of skill inthe art of organic synthesis. Described below are examples of suchprocedures.

Methods for obtaining compounds wherein R⁵ is OH and R⁶ is OR²¹ includeprotection of nitrogen, if necessary, followed by reaction of the diolwith one equivalent of base and one equivalent of acyl halide, alkylhalide, alkoxyalkyl halide, alkoxycarbonyl halide, benzoyl halide,diphenyl carbonate or phenylisocyanate, and purification by columnchromatography of the unwanted bis-alkylated and unreacted material.

Methods for obtaining compounds wherein R⁵ is OH and R⁶ is H includeprotection of nitrogen, if necessary, and reduction of the diol to themonool using techniques known in the art (see, for example, Chem. Comm.1971, 1097; J. Org. Chem. 1969, 3923). The preferred method is formationof cyclic diol ester and reduction using hydride. Deprotection ofnitrogen, if necessary, results in the desired compound.

Methods for obtaining compounds wherein R⁵ is OH and R⁶ is F includeprotection of nitrogen, if necessary, followed by formation ofmono-protected diol as described above. Reaction with a fluorinatingagent, preferably diethylaminosulfurtrifluoride (DAST) (Reagents forOrganic Synthesis, Vol. 13, p. 110, Wiley Interscience, NY, 1988),provides the alkyl fluoride. Deprotection of nitrogen, if necessary, andhydroxyl results in the desired compound.

Methods for obtaining compounds wherein R⁵ is OH and R⁶ is ═O includeprotection of nitrogen, if necessary, and standard conditions foroxidizing glycols to pinacols. The preferred oxidant is one equivalentof pyridinium dichromate in dichloromethane, or one equivalent of NaOClin HOAC. Deprotection of nitrogen, if necessary, results in the desiredcompound. Alternatively, a monohydroxy compound described above can beoxidized to the ketone under standard conditions, preferably Swernoxidation using oxalyl chloride, DMSO and Et₃ N, followed byalpha-hydroxylation of the ketone (see Tet. Lett. 1981, 607; Tet. Lett.1982, 2917).

Methods for obtaining compounds wherein R⁵ is OH and R⁶ is difluoroinclude protection of nitrogen, if necessary, and hydroxyl of the aboveobtained pinacol, followed by reaction of the carbonyl with afluorinating reagent, such as DAST. Deprotection of hydroxyl andnitrogen, if necessary, results in the desired compound.

Methods for obtaining compounds wherein R⁵ and R⁶ join to form anepoxide include protection of nitrogen, if necessary, followed bystandard conditions for the formation of an epoxide from a glycol (see,for example, J. Org. Chem. 1981, 3361). Preferred is the reaction of theglycol with more than 2 equivalents of base and one equivalent of anactivating group, such as methanesulfonyl chloride. Deprotection ifnecessary results in the desired compound.

Methods for obtaining compounds wherein R⁵ is OH and R⁶ is C₁ -C₃ alkylinclude protection of nitrogen, if necessary, and reaction of theepoxide prepared above with C₁ -C₃ alkylmetal reagents. Preferred is thereaction of lithium dialkyl cuprates in aprotic solvents at lowtemperatures (-78° to -40° C.) (see Carruthers, Some Modern Methods inOraanic Synthesis, p. 64, Cambridge University Press, 1978).

With a judicious selection of reagents, as is well appreciated to oneskilled in the art, these manipulations can be performed in astraightforward manner to yield the claimed combinations of R⁵ and R⁶.

Compounds of the invention wherein:

W is --N(R²²)C(═Z)N(R²³)-- or --N(R²²)C(═O)C(═O)N(R²³)-- or--N(R²²)S(═Z')N(R²³)-- or --N(R²²)S(═Z)₂ N(R²³)-- or--N(R²²)P(═O)(R^(24a))N(R²³)-- or --N(R²²)C(F₂)C(═O)N(R²³)-- or--N(R²²)C(F₂)S(═O)N(R²³)-- or --N(R²²)P(--Z)N(R²³)--, and n is 0;

can be synthesized from diamines of formula (V): ##STR25## which can inturn be synthesized as described in European Patent ApplicationPublication Number 402 646 A1.

Protection, if necessary, cyclization, and functional group manipulationif desired is performed as described above to obtain compounds ofstructure (VI): ##STR26##

Compounds of the invention wherein:

W is --OC(═O)O-- or --C(═Z)-- or--C(R²⁵)(R²⁶)P(═O)(R^(24a))C(R²⁷)(R²⁸)-- or --P(═O)(R^(24a))-- and n is1;

can be formed from diols of structure (VII): ##STR27## which can in turnbe synthesized as described in copending, commonly assigned U.S. patentapplication Jadhav et al. U.S. Ser. No. 07/714,042, filed May 31, 1991.

Functional group manipulation, if desired, may be performed as describedabove, followed by cyclization to the carbonate using standardconditions, preferably phosgene or thiophosgene in the presence of 2equivalents of a base such as potassium hydride, to obtain compounds ofstructure (I).

Compounds of the invention wherein:

W is --N(R²²)C(═Z)O-- or N(R²²)P(═O)(R^(24a))C(R²⁷)(R²⁸)-- or--C(R²⁵)(R²⁶)P(═O)(R^(24a))O-- and n is 1;

can be formed from aminoalcohol of structure (VIII): ##STR28## which canin turn be synthesized as described in a copending, commonly assignedU.S. patent application Jadhav et al. U.S. Ser. No. 07/714,042, filedMay 31, 1991, by employing a single equivalent of azide in the reactionof the diol of formula (VII) to obtain the azidoalcohol, followed byreduction as described in U.S. Ser. No. 07/714,042, to form theaminoalcohol.

Protection, if necessary, and functional group manipulation, if desired,is performed as described above, followed by cyclization to thecarbamate using standard conditions, preferably phosgene or thiophosgenein the presence of 2 equivalents of a base, such as potassium hydride,to obtain compounds of structure (I).

Compounds of the invention wherein:

W is --OC(═Z)O-- and n is 0;

can be formed from the diol of structure (IX): ##STR29## which can inturn be synthesized by the reaction of R⁴ CHO with the lithium anion of1,3 dithiane, followed by the reaction of R⁷ CHO with the anion of theproduct (see Carruthers, Some Modern Methods in Organic Synthesis, p.45, Cambridge University Press, 1978). Cleavage of the dithiane withmercuric ion yields the acyclic alpha, alpha' dihydroxyketone.

Functional group manipulation, if desired, is performed as describedabove, followed by cyclization to the carbonate using standardconditions, preferably phosgene or thiophosgene, in the presence of 2equivalents of a base such as potassium hydride, to obtain compounds ofstructure (I).

Compounds of the invention wherein:

W is --N(R²²)C(═Z)O-- and n is 0;

can be formed from aminoalcohol of structure (X): ##STR30## which can inturn be synthesized by the techniques described in European PatentApplication Publication Number 402 646 A1 for the synthesis of compoundsof structure (V), above; however, in place of azide, in opening theoxirane (shown below), an oxygen nucleophile, such as acetate orhydroxide ion, is reacted in the presence of a polar aprotic solvent,such as DMSO. ##STR31##

Alternatively, the oxirane is treated with a catalytic amount of astrong acid in water and a cosolvent, if necessary, which technique alsoremoves the BOC protecting group.

Protection, if necessary, and functional group manipulation, if desired,is performed as described above, followed by cyclization to thecarbamate using standard conditions, preferably phosgene or thiophosgenein the presence of 2 equivalents of a base such as potassium hydride, toobtain compounds of structure (I).

Compounds of the present invention wherein:

W is --C(R²⁵)(R²⁶)N(CH₃)(O)C(R²⁷)(R²⁸)--;

can be synthesized from aminoalcohols (VIII) and (X) by the followingsteps: protection of nitrogen, if necessary, preferably with abenzyloxycarbonyl group; activation of the alcohol to displacement,preferably with a sulfonate derivative, such as mesyl chloride; removalof the nitrogen protecting group, preferably with hydrogen in thepresence of a catalyst, such as palladium on carbon; and heating underdilute conditions in the presence of a base such as triethylamine toeffect cyclization.

The secondary cyclic amine is then methylated, preferably with formicacid/formaldehyde, and oxidized, preferably with a peracid, such asMCPBA, to form compounds of formula (I), wherein W is--C(R²⁵)(R²⁶)N(CH₃)(O)C(R²⁷)(R²⁸)--. The secondary cyclic amine canalternatively be directly oxidized to form structure (I), where W is--C(R²⁵)(R²⁶)N(OR²⁹)C(R²⁷)(R²⁸)--.

Compounds wherein:

W is --C(R²⁵)(R²⁶)C(═Z)C(R²⁷)(R²⁸)-- and n is 0;

can be prepared by the alkylation of protected cyclohexanedione (XI)with the required R⁴ -LG and R⁷ -LG, and optionally R^(4A) -LG andR^(7A) -LG groups, wherein LG represents a leaving group such as halogenor sulfonate ester. ##STR32##

Reduction of the ketone to the alcohol, preferably with LiAlH₄, ormanipulation to other values of R⁵ as described above, is followed bycleavage of the ketal (see Greene and Wuts, Protective Groups in OrganicSynthesis, Chapter 2, Wiley, NY, 1991). Protection of the alcohol orother reactive groups, followed by alkylation ketone and deprotection,provides compounds of structure (I), wherein W is--C(R²⁵)(R²⁶)C(═Z)C(R²⁷)(R²⁸)-- and n is 0.

Compounds wherein:

W is --C(R²⁵)(R²⁶)C(═Z)C(R²⁷)(R²⁸)-- and n is 1;

can be prepared from the protected hydroxyketones described immediatelyabove by ring expansion, for example via the Tiffeneau-Demyanov reaction(March, Advanced Organic Chemistry, p. 965, Wiley, NY, 1985), or bytreatment with dimethylsulfonium ylide to form the spiro-epoxide,followed by acid-catalyzed ring expansion to the cycloheptanone (ibid.,pp. 871, 966).

The above routes have the advantage of producing a number ofstereoiomers which, upon purification, can be evaluated for the bestcombination of potency, safety and in vivo availability.

Compounds wherein:

W is --C(R²⁵)(R²⁶)C(F₂)C(R²⁷)(R²⁸)-- and n is 0 or 1;

can be obtained from the above-described protected hydroxyketone bytreatment with a fluorinating reagent, preferably DAST, as describedabove.

Compounds wherein:

W is --N(R²²)C(═Z)C(R²⁷)(R²⁸)-- and n is 0;

can be obtained by cyclization of compound (XII) to the lactam usingtechniques known in the art (March, Advanced Organic Chemistry, p. 371,Wiley, NY, 1985). ##STR33##

Compounds of structure (XII) can in turn be obtained as described inEuropean Patent Application Publication Number 434 365 A2, EuropeanPatent Application Publication Number 386 611 A2, European PatentApplication Publication Number 389 127 A1, and CA 2005337, each of whichare hereby incorporated by reference. OP in structure (XII) designatesprotected oxygen. Hydroxyl can be protected by the use of any of anumber of groups as described in Greene and Wuts, Protective Groups inOrganic Synthesis, Chapter 2, Wiley, NY (1991).

If desired, the resulting lactam (XIII): ##STR34## can be furtherfunctionalized, for example by the following techniques: the lactamnitrogen can be alkylated with an R²² -LG group, preferably employingsodium hydride in DMF; an R^(4A), R⁷ or R^(7A) group can be added bydeprotection and oxidation of the alcohol, followed by alkylation of theenolate using R^(4A) -LG, R⁷ -LG or R^(7A) -LG; and reduction of theketone to hydroxyl or otherwise functionalizing to obtain the R⁵ groupof choice as described above.

Compounds wherein:

W is --N(R²²)C(═Z)C(R²⁷)(R²⁸)-- and n is 1;

can be obtained through techniques known in the art from ketones ofstructure (I) wherein W is --C(R²⁵)(R²⁶)C(═Z)C(R²⁷)(R²⁸)-- and n is 0,preferably via the Beckmann rearrangement (March, Advanced OrganicChemistry, p. 987, Wiley, NY, 1985). Manipulation of the R⁵ group, ifdesired, as described above provides R⁵ and R⁶ -substituted examples of(I), wherein W=--N(R²²)C(═Z)C(R²⁷)(R²⁸)-- and n=1.

Compounds wherein:

W is --C(R²⁵)(R²⁶)C(═Z)O-- and n is 0 or 1;

can be obtained from compounds of structure (I), whereinW=--N(R²²)C(═Z)C(R²⁷)(R²⁸)--, n=0 or 1, and R²² =H, for example, byhydrolysis of the lactam, followed by displacement of the primary amineby hydroxyl, and closure to the lactone (March, Advanced OrganicChemistry, p. 348, Wiley, NY, 1985).

Similarly, compounds wherein:

W is --C(R²⁵)(R²⁶)C(═Z)S-- and n is 0 or 1;

can be obtained from compounds of structure (I), whereinW=--N(R²²)C(═Z)C(R²⁷)(R²⁸)--, n=0 or 1, and R²² =H, for example, byhydrolysis of the lactam, followed by conversion of the primary amine tothe diazonium salt, displacement by NaSH, and closure to the thiolactone(March, Advanced Organic Chemistry, p. 601, Wiley, NY, 1985).

Compounds of structure (I) described above wherein Z=O can be convertedto the thio derivatives, Z=S. using standard conditions (March, AdvancedOrganic Chemistry, p. 792, Wiley, NY, 1985); preferred is the use of thedisulfide described in Bull. Soc. Chim. Belges 1978, 223.

Structures (I) described above wherein Z=O can be converted to the iminoderivatives, Z=NR²⁴, using standard conditions. When R²⁴ is OH orO-alkyl, the oximes can be formed and alkylated if desired as describedin March, Advanced Organic Chemistry, pp. 359, 805, Wiley, NY, 1985. Thehydrazones and imines can be formed similarly (ibid, pp. 533, 797).

The compounds of the formula (I) where inW=--N(R²²)P(O)(R^(24a))N(R²³)-- and n=1, and R^(24a) is ethyl, can besynthesized by cyclization of diamine III under conditions normally usedto form cyclic phosphoric amides, as exemplfied by Patois et al. inHeteroatom. Chem. 1(5), 369-374, (1990), wherein ethylphosphorodichloridate in presence of trialkylamine, such astriethylamine, was used to cyclize a diimino derivative. Similarly,other diimines could be cyclized to form cyclic phosphoric amidederivatives.

It is expected that the compounds of the invention can also be preparedas shown in Scheme 1 (shown below). The intra-molecular coupling of theN-substituted or unsubstituted dialdehydes may be achieved byorganometal reagents derived from vanadium, titanium, samarium etc. Thedialdehyde precursors can be prepared from the commercially availablematerials by the methods known to those skilled in the art of organicsynthesis, preferably by the techniques disclosed in copending commmonlyassigned U.S. Patent Application, Hodge, U.S. Ser. No. 07/659,442, filedFeb. 21, 1991.

Compounds wherein W is --N(R²²)C(═O)N(R²³)--0 and n is 2 can besynthesized as shown in Scheme 2 (below). The eight-membered cyclic ureain Scheme 2 can be protected, if necessary, and manipulated as describedabove to yield the desired compounds.

Compounds wherein W is --N(R²²)C(═O)N(R²³)-- and n is 1 can likewise besynthesized as shown in Schemes 3, 4, 6, 7 (below). If necessary,intermediates described herein can be manipulated by methods known tothose skilled in the art of organic synthesis to provide compoundswithin the scope of the invention.

Compounds wherein W is --N(R²²)C(═N--OR)N(R²³)-- or--N(R²²)C(═S)N(R²³)-- and n is 1 can be synthesized as shown in Scheme 5(below). If necessary, intermediates described herein can be manipulatedby methods known to those skilled in the art of organic synthesis toprovide compounds within the scope of the invention.

Compounds wherein W is --N(R²²)C(═O)N(R²³)-- and n is 0 can likewise besynthesized as shown in Scheme 8 (below). If necessary, intermediatesdescribed herein can be manipulated by methods known to those skilled inthe art of organic synthesis to provide compounds within the scope ofthe invention.

Compounds wherein W is --N(R²²)C(═O)N(R²³)--, n is 0 and R²³ and R³³ arecombined to be a direct bond, can be synthesized as shown in Scheme 9.Compounds of (XXXIIa) were treated under strongly ionizing conditions toproduce compounds where W is --N(R²²)C(═O)N(R²³)--, n is 0, and R²³ isH, R³³ is --O₂ C-alkyl. Treatment of compound (XXXIIa) with hydrogen andpalladium catalyst provided R³³ is H, whereas treatment with gaseoushydrogen bromide provided R³³ is Br. Another route to these compoundswas developed (Scheme 10). If necessary, intermediates described hereincan be manipulated by methods known to those skilled in the art oforganic synthesis to provide compounds within the scope of theinvention.

Compounds wherein W is --N(R²²)S(═O)2N(R²³)--, n is 1 could besynthesized as shown in Scheme 11. Diamines of structure (III) weretreated with sulfamide to give the cyclic sulfamides. Alkylation using ametal hydride base gave the bisalkylated products. The monoalkylatedproducts could be obtained by selective alkylation using techniquesknown to one skilled in the art of orgainc synthesis and furtherdescribed in this invention.

Compounds wherein W is --C(R²⁵)(R²⁶)SC(R²⁷)(R²⁸)--,--C(R²⁵)(R²⁶)S(═Z')C(R²⁷)(R²⁸)-- and --C(R²⁵)(R²⁶)S(═Z')₂ C(R²⁷)(R²⁸)--,n is 1, and Z' is defined above can be synthesized as shown in Scheme12. Asymmetric epoxidation of muconic acid (Sharpless et al., J. Org.Chem. 57, 2768 (1992)); followed by benzylation (Seebach, D. andWasmuth, D. Hely. Chim. Acta 63, 197 (1980)) provides a secondary diol,which can be converted to primary diol (XXXVIIa) by protection andreduction with lithium aluminum hydride. Further elaboration by themethods of Dugger et al. (Tetrahedron Letters 33, 6763 (1992)) and Trostet al. (Tetrahedron Letters, 22, 1287 (1981)) provide the sulfoxideshown. Further oxidation using a stronger oxidizing agent such asm-chloroperbenzoic acid would provide the corresponding sulfone (W is--C(R²⁵)(R²⁶)S(═O)₂ C(R²⁷)(R²⁸)--). The intermediates described thereincan be manipulated by methods known to those skilled in the art oforganic synthesis to provide compounds within the scope of theinvention.

Compounds wherein W is --C(R²⁵)(R²⁶)C(═Z)C(R²⁷)(R²⁸)--, n is 1, and Z isdefined above can be synthesized as shown in Scheme 13. Compound XXXVIIacould be converted to the corresponding dibromide using carbontetrabromide/triphenylphosphine. Dithiane anion, formed according to themethod of Seebach, as reported in Org. Syn., Coll. Vol. 6, 316 (1988),could be alkylated with this dibromide. The seven-membered ring ketone(Z is O), upon liberation with aqueous mercuric ion, could be alkylatedaccording to methods reported in the literature. Imines (Z is NR²⁴) andthiocarbonyls (Z is S) can be prepared by one skilled in the art oforganic synthesis using methods described in the literature.

Compounds wherein W is --C(═Z)--, n is 1, and Z is defined above can besynthesized as shown in Scheme 14. Secondary diol (VII) could beconverted to the dibromide using such as described previously. Dithianealkylation followed by deprotection with mercury ion would produce thefive-membered ring ketone. Alkylation of the alpha-carbons would providefor substitution at R^(4A) and R^(7A). Thiocarbonyls and imines of thecarbonyl could be prepared using methods described in the literature.

Compounds wherein W is --C(R²⁵)(R²⁶)P(═O)(R^(24a))N(R²³)-- or--C(R²⁵)(R²⁶)P(═O)(R^(24a))O-- and n is 1, could be prepared as shown inScheme 15. Aminoalcohol (VIII) could be converted to the correspondingbromide using the method of Morin and Sawaya (Synthesis, (1987), 479)and displaced with lithiophosphinate according to the method of Coreyand Kwiatkowski (J. Amer. Chem. Soc., (1966), 88, 5654). Deprotection ofthe amine protecting group would be followed by phosphoramide formationaccording to the method described by Patel et al., (Tet Lett., (1990),31, 5591). Alkylation with strong base would lead to the compounds whereW is --C(R²⁵)(R²⁶)P(═O)(R^(24a))N(R²³)--. Similarly, diazotization andnucleophilic displacement with hydroxide would lead to the compoundswhere W is --C(R²⁵)(R²⁶)P(═O)(R^(24a))O-- after cyclization.

Compounds wherein W is --C(R²⁵)(R²⁶)P(═O)(R^(24a))C(R²⁷)(R²⁸)-- or--P(═O)(R^(24a))-- and n is 1, could be prepared as shown in Scheme 16.Secondary diol (VII) could be brominated by the method of Morin andSawaya to give (XXXVIa), which could be elaborated to (XXXVIIIa) viaearlier described (XXXVIIa). Grignard coupling with methyldichlorophosphate using the method of Polniaszek and Foster (J. Org.Chem., 1991, 56, 3137) would lead to a cyclic phosphinate. Alkylationwith strong base based on methods described in the literature (i.e., seePolniaszek above) would provide the desired products.

Compounds of formula (I) wherein W is --(R²²)N⁺ ═C(R³⁶)N(R²³)-- and--N═C(R³⁶)N(R²³)-- and n=1 can be prepared according to Scheme 17.Intermediate (XXXIXa) can be cyclized under standard amidine reactionconditions, based on method known in the art. Quaternary salt formationwith alkyl halide leads to compounds of the formula (XXXIXd) and(XXXIXe), which can be acid-deprotected according to method describedherein.

Synthesis of intermediate (XLa) is described in Scheme 18a, and usethereafter is described in Schemes 18b-18c. N-Cbz-Phenylalaninal (XL')is prepared from optically-active phenylalanine (XLa') by the routepreviously described. Compound (XLc') can be prepared by the reaction of(XLb') with an appropriate acetic acid anion equivalent such as aReformatsky reagent derived from ethyl bromoacetate (prepared frombromoethyl acetate and zinc metal). Other acetic acid anion equivalentsare contemplated and are recognized by those possessing skill in theart. Compound (XLd') can be prepared by reacting (XLc') with an acylanion equivalent such as a dithiane anion (such as that derived from1,3-dithiane upon reaction with butyllithium). Other acyl anionequivalents are contemplated and are recognized by those possessingskill in the art. The conversion of (XLc') to (XLd') can alsoincorporate the use of either or both oxygen-protecting groups andnitrogen-protecting groups. A suitable oxygen-protecting group is theSEM (trimethylsilylethyloxymethyl) ether and a suitablenitrogen-protecting group is the Cbz (carbobenzyloxy) carbamate. Otherprotecting groups are contemplated including those described inProtecting Groups in Organic Synthesis, Second Edition by T. W. Greeneand P. G. M. Wuts, John Wiley & Sons Inc., 1991. Compound (XLa) can beobtained by the hydrolysis of (XLd') with acid or base.

Alternatively, (XLa) can be obtained as follows: (XLe') can be preparedby reaction of (XLb') with a pyruvic acid anion equivalent such as aReformatsky reagent. Other pyruvic acid anion equivalents arecontemplated and are recognized by those possessing skill in the art.(XLf') is prepared by the reaction of (XLe') with an alkyl or arylderived nucleophile such as a Grignard reagent or an organolithiumreagent (such as benzylmagnesium bromide or phenyllithium). Otherorganometallic species are contemplated and are recognized by thosepossessing skill in the art. Intermediate (XLa) can be obtained byreaction of (XLf') under hydrolytic conditions needed to induce estercleavage and/or conditions necessary to remove any or all protectinggroups.

Intermediates (XLa)-(XLk) can be derived from (L)-phenylalanine, forexample, although all other naturally-occurring and other unnaturalamino acids are also contemplated.

Intermediate (XLb) can be prepared by the reaction of a methylenechloride solution of compound (XLa) with SEM-Cl(trimethylsilylethyloxymethyl chloride) in the presence of an amine base(such as diisopropylethylamine). Intermediate (XLc) can be obtained bythe reaction of (XLb) with a carboxylic acid activating reagent such asdicyclohexylcarbodiimide (DCC). Other peptide-forming conditions andreagents are contemplated and are recognized by those possessing skillin the art. Intermediate (XLd) can be obtained by the reaction of (XLc)with an appropriately protected (if needed) hydroxymethylbenzyl halidefollowed by the removal of the SEM protecting groups via reaction withfluoride ion (tetrabutylammonium fluoride) in a suitable solvent(tetrahydrofuran).

Intermediate (XLe) is obtained by the reaction of (XLa) with SEM-Clunder conditions to avoid/suppress bis-alkylation such as limiting molarequivalents of SEM-Cl and/or using lower reaction temperatures.Intermediate (XLf) can be obtained reaction of (XLe) with phosgene inthe presence of a suitable base. Phosgene equivalents and various aminebases are also contemplated and are recognized by those possessing skillin the art. Compounds of the formula (XLg) can be obtained by the samemethodology described above for the preparation of (XLd) from compound(XLc).

Compounds (XLh) can be obtained by reacting (XLb) with Cbz--Cl(carbobenzyloxy chloride) in the presence of a base. Intermediate (XLi)can be obtained by reacting (XLh) with a carboxylic acid activatingreagent in the presence of an amine such as ammonia. Other methods arecontemplated and are recognized by those possessing skill in the art.Compound (XLj) is obtained by the reaction of (XLi) with a carbonmonoxide equivalent such as phosgene in the presence of an amine base aspreviously described for the conversion of (XLe) to (XLf). Compounds ofthe formula (XLk) can obtained by N-alkylation and removal of protectinggroup(s) as described for the conversion of (XLc) to (XLd).

A more detailed description of the general formulas is provided inScheme 18c.

Compounds such as lactam (XLIm) with an alkoxy substituent could besynthesized as shown in Scheme 19. The alcohol (XLIh) obtained using theprocedure of S. Thaisrivongs, et al (J. Med. Chem. 1991, 34, 2344-2356)can be alkylated with benzyl bromide using standard procedures to give(XLIi). Treatment with catalytic p-toluene-sulfonic acid in methanolcleaves the oxazolidine to give the free alcohol (XLIj) which can bethen converted to the acid (XLIk) using the procedure described by S.Thaisrivongs, et al (J. Med. Chem. 1991, 34, 2344-2356). Protection ofthe alcohol as the t-butyldimethylsilyl ether and cyclization to thelactam is analogous to that described in Scheme 23.

Compounds such as the cyclohexane fused 7-membered ring lactam (XLIIh)could be synthesized as outlined in Scheme 20. The acid (XLIIa) isobtained following the procedure of J. A. Martin and G. J. Thomas (EP 0512 343 A2). This can be treated with methanol and catalyticp-toluenesulfonic acid to give the free alcohol which can be protectedas the t-butyldimethylsilyl ether to give the acid (XLIIc). Thecyclization to the fused lactam (XLIIf) followed by an alkylationdeprotection sequence can lead to (XLIIh)

Compounds of formula (XLIII) can be converted to a variety of cyclicstructures and the general outline of useful routes is detailed inSchemes 21, 21a and 21b. Advanced intermediates (XLIIIh) and (XLIIIn)are known and details of their preparation are described in WO9301166-A(published 21 Jan. 1993), herein incorporated by reference. Theconversion of (XLIIIa) via known methodology and that described herein,to a 6-memebered cyclic structure (XLIIIg), wherein P denotes a suitablehydroxyl protecting group (for example 2-(trimethylsilyl)ethoxymethyl(SEM), 2-methoxyethyl (MEM)) and X can be NH, O. R and R' are similar toR⁴ and R⁷. Further alkylation of the nitrogens can be performed.Conversion of (XLIIIh) to a 7-membered cyclic structure via knownsynthetic transformations is described, wherein P denotes a suitableprotecting group (for example SEM, MEM) and R and R' are similar to R⁴and R⁷. X and X' can be any nucleophile (nucleophilic carbon, nitrogen,oxygen, sulfur). Conversion of intermediate (XLIIIn) to an 8-memberedcyclic structure (XLIIIs) is described. P denotes an appropriateprotecting group; R and R' are similar to R⁴ and R⁷ and X can be anynucleophile; X' can be NH, O.

Compounds such as the benzo-fused 7-membered ring lactam (XLIVh) can besynthesized as outlined in Scheme 22. The acid (XLIVa) is obtainedfollowing the procedure of M. Hammond and S. W. Kaldor (EP 0 526 009A1). The free alcohol can be protected as the t-butyldimethylsilyl etherto give the acid (XLIVc). The cyclization to the fused lactam (XLIVf)followed by an alkylation deprotection sequence can generate (XLIVh) byanalogy to that described for Scheme 23.

Compounds of Formula (I) wherein, W is N(R²²)C(═O)C(R²⁷)(R²⁸), n is 0and R⁷ is hydrogen, and R⁴ and R²⁷ are benzyl can be synthesizedaccording to Scheme 23. Conversion of N-Boc-phenylalanine by an 8 stepprocedure can give intermediates of the formula (XLVa). Hydrolysis ofthe lactone, followed by activation of the acid functionality usingmethods known in peptide chemistry, followed by deprotection of theamine protecting group and intramolecular cyclization can give lactam(XLVe). Standard alkyation and alcohol liberation provide compounds ofthe formula stated above.

The preparation of compounds of the formula (XLVId) is shown in Scheme24. The Wittig product from the first step is reduced to the allylicalcohol using DIBAL-H in methylene chloride at -78° C. This alcohol canbe epoxidized using m-chloroperbenzoic acid or using Sharplessepoxidation methodology to give the epoxy alcohol (XLVIa). The epoxidecan be opened selectively using TMSN₃ (Sharpless, K. B. J. Org, Chem(1988) 53 5185) to give the desired 1,2-diol. Exhaustive silylationfollowed by selective deprotection of the primary silyl ether givescompound (XLVIb). Standard primary tosylate formation followed bydisplacement with sodium azide can give the diazide (XLVIc). Reductionof the diazide using catalytic hydrogenation and cyclization usingcarbonyl diimidazole would give the 6-membered cyclic urea. Alkylationas described herein and deprotection would give the final product(XLVId). The diazide (XLVIc) can be manipulated to give a variety ofcyclic structures as previously shown.

Compounds of the formula (I), wherein W=--R²² NC(═O)NR²³ --, n is 1, R⁵is OH or ═O and R⁶ =R^(6a) is fluorine, can be synthesized as shown inScheme 25. Compound (XLVIIa) can be oxidized to the corresponding ketoneby Jones oxidation (Org. Syn. Coll., Vol. V, 866) followed by reactionof the carbonyl with a fluorinating agent such as DAST. Deprotection,cyclization, alkylation and removal of hydroxyl protecting groups (suchas MEM) can give (XLVIIg), which can be further oxidized to (XLVIIh)using the method of Gallina & Giordano (Synthesis 1989, 466).

The preparation of compounds of the formula (XLVIIIc) is shown in Scheme26. Starting from the known hydroxy ketone (XLVIIIa) (WO 92/00956,published Jan. 23, 1992) the alcohol can be protected and the aminefunction deprotected to give diamine (XLVIIIb). Cyclization andintroduction of the R²² and R²³ can be accomplished as described herein.Reduction of the ketone and deprotection can give the desired diol(XLVIIIc). Hydroxy ketone (XLVIIIa) can be converted to the triol(XLVIIIe). After alcohol protection, a second hydroxyl group can beintroduced α to the ketone using standard chemical procedures known toone skilled in the art. After protecting this hydoxyl, the amines can bedeprotected to give diamine (XLVIIId).

Using similar chemistry as discussed previously, the triol (XLVIIIe) canbe prepared as shown in Scheme 26a. The mono-ol (XLVIIIj) can beprepared starting from the aldehyde (XLVIIIf) and an organometallicreagent (XLVIIIg). Both of these compounds can be prepared from aminoacids using standard chemical procedures known to one skilled in theart. The alcohol (XLVIIIh) can be protected and manipulated as discussedpreviously to give the desired mono-ol (XLVIIIj).

The cyclic carbonates of the formula (XLIXb) can be prepared, as shownon Scheme 27, starting from commercially available3,4-O-Isopropylidene-D-mannitol. Primary tosylate formation and basetreatment can provide the diepoxide which can be opened with numerousnucleophiles to give compounds of the formula (XLIXa). Cyclization anddeprotection would give the desired diol (XLIXb).

Compounds wherein W is --N(R²²)P(O)(R^(24a))N(R²³)--, n=1 and R^(24a) isphenoxy or OH, can be synthesized as described earlier and as shown inScheme 28. Diamine III could be cyclized with phenyldichlorophosphateusing the method of Patois et al. (Heteroatom. Chem. 1990, 1, 369) togive the cyclic phosphoric amide. Alkylation with strong base andremoval of the protecting groups using methods known to one skilled inthe art would give the desired products.

Compounds of the formula (I) wherein W is --N(R²²)C(═O)N(R²³)--, and R²²and R²³ are NH(R^(22a)) and NH(R^(23a)), respectively, can be preparedas shown in Scheme 29. Intermediate (XXIc) can be treated withchloramine to yield dihydrazine (LIa) according to the method of S. R.Sandler and W. Karo (Organic Functional Group Preparations, Vol 1,Academic Press, N.Y., 1983, p.445), herein incorporated by reference.Cyclization using phosgene can give cyclic urea (LIb). Standardprocedure for alkylation and deprotection can provide alkylateddihydrazine (LIc). Alternatively, (XXIc) can be treated withchloroaminobenzene, according to the method of S. R. Sandler and W. Karoabove, to yield dihydrazine (LId). Cyclization using phosgene, followedby alkylation of the product as described previously, can providecompounds of the formula (LIe).

Compounds of the formula (I), wherein W is --N(R22)C(═C(CN)2)N(R23)--and n=1, can be prepared as shown in Scheme 30. Intermediate (XXIc) canbe treated with 1,1'-bismethylthio-2,2'biscyanoethylene in acetonitrile,followed by the standard procedure of alkylation and deprotection togive compounds of the formula (LIIa).

Compounds of the formula (I), wherein W is --N(R²²)C(═S)N(R²³)--, R²²and R²³ are not hydrogen, and n=1, can be prepared as shown in Scheme31. Mono-alkylated intermediate (XXVIIb) can be further reacted with aalkyl bromide under refluxing reaction conditions (to facilitate theremoval of byproduct methyl bromide) to give dialkylated thiocarbonylcompound (LIIIa), which can be acid-deprotected as described previously.

Compounds of the formula (I), wherein W is --N(R²²)C(═O)C(R²⁷)--, n=1,and R28 and R7a are taken to form a bond can be prepared as shown inScheme 32. The aldehydes required for coupling can be prepared bymethods known to one of skill in the art. Acetylation after coupling canprovide diacetate (LIVa). Amine protecting group modification can leadto (LIVb), afterwhich liberation of the carbonyl (LIVb) and Wittigolefination using stabilized Wittig can provide (LIVc), after separationof the geometric isomers. Liberation of the amine protecting group canprovide (LIVd), which upon modification of the ester for standardamino-acid type coupling (via LIVe) can lead to compounds of formula(LIVf).

The synthesis of compounds of the invention is described in furtherdetail below.

PROCEDURE 1

Preparation of di-N-CBZ protected 1,4-diamino-2,3-diols (XIX): ##STR35##

Detailed experimental procedures for the synthesis of compound (XIX) aredescribed in copending commonly assigned patent application Jadhav etal. U.S. Ser. No. 07/714,042, filed May 31, 1991.

PROCEDURE 2

Preparation of di-O protected di-N-CBZ 1,4-diamino diols (XXa) and(XXb): ##STR36##

A. Protection as 2-(trimethylsilyl) ethoxy methyl (SEM) ether (XXa):

Compound (XIX) (60 g, 105 mmol) was dissolved in dry DMF (600 mL).Diisopropylethylamine (75 mL) and SEMCl (66.8 g, 400 mmol) were addedand the mixture stirred for 16 h at room temperature under N₂. Thesolution was diluted with water (1 L) and extracted with hexane (400mL). The organic layer was separated and washed with water (2×100 mL).The aqueous layers were combined and extracted with hexane (2×300 mL).The organic layers were combined, washed with water (2×100 mL), driedover MgSO₄, filtered and evaporated. The residue was chromatographed onSiO₂ and eluted with 10-30% ethyl acetate/hexane to afford a white solid(91 g, 100%). NMR(CDCl₃): δ 7.0-7.4 (m, 20H, Ph), 5,01 (br s, 4H, PhCH₂CO), 4.5-4.95 (m, 6H, NH, OCH₂ O), 3.6-4.25 (m, 4H, CHOCH₂, CHNH), 3.5(s, 4H, OCH₂ CH₂), 2.76 (br d, 4H, PhCH₂), 0.8-1.0 (m, 4H, SiCH₂). MS:846 (M+NH₄, 100), 695 (M-SEM, 40).

B. Protection as methoxymethyl (MOM) ether (XXb).

Compound (XIX) (0.50 g, 0.88 mmol) was dissolved in dry DMF (10 mL).Diisopropylethylamine (0.46 mL, 2.64 mmol) and methoxymethyl bromide(0.165 mL, 2.02 mmol) were added and the solution stirred at 40° C.under nitrogen for four h. TLC (50/50 ethyl acetate/methylene chloride)showed that the reaction was complete. The mixture was partitionedbetween methylene chloride (50 mL) and 5% HCl (30 mL). The organic layerwas separated, washed with water (5×20 mL), brine (20 mL), dried overMgSO₄, filtered and evaporated to a light yellow oil. Chromatography onSiO₂ and elution with 1-20% ethyl acetate/methylene chloride afforded(XXb) as a clear oil (0.29 g, 53%).

NMR (CDCl₃): δ 6.95-7.42 (m, 20H, Ph), 5.1-3.8 (m, complex), 3.35 (s,6H, OCH₃), 2.8-2.95 (m, 4H, PhCH₂). MS: 657 (13, M+1), 674 (21, M+NH₄),522 (84), 414 (100), 370 (34).

PROCEDURE 3

Deprotection of amines (XXa) and (XXb) via hydrogenation to afford(XXIa) and (XXIb): ##STR37##

A. Hydrogenation of SEM ether (XXa).

Compound (XXa) (90 g, 108.5 mmol) was dissolved in absolute ethanol (2.5L). 5% Pd/C (6.5 g) was added and the solution was stirred underhydrogen for 1.5 h until -hydrogen uptake ceased. TLC (20/80 ethylacetate/hexane) showed that the reaction was complete. The solution wasfiltered through Celite and evaporated at reduced pressure to give XXIaas a colorless gum (60 g, 99%).

NMR (CDCl₃): δ 7.1-7.35 (m, 10H, Ph), 4.72 (br d, 4H, OCH₂ O), 3.5-3.9(m, 6H, NH₂, CHOCH₂), 3.15 (m, 2H, CHNH₂), 2.55-2.95 (m, 4H, PhCH₂),0.95 (m, 4H, SiCH₂).

B. Hydrogenation of MOM ether (XXb).

Compound (XXb) (0.29 g, 0.441 mmol) was dissolved in ethyl acetate (6mL) and methanol (3 mL). 10% Pd/C (70 mg) was added and the solutionstirred under hydrogen until H₂ uptake ceased. TLC (20/80 methanol/ethylacetate) showed that the reaction was complete. The solution wasfiltered through Celite and evaporated at reduced pressure to affordXXIb as a clear oil (0.132 g, 77.4%). NMR (CDCl₃): δ 7.1-7.35 (m, 10H,Ph), 4.58 (s, 4H, OCH₂ O), 3.75 (br s, 2H, CHOCH₂), 3.3-3.5 (m, 2H,CHNH₂), 3.23 (s, 6H, OCH₃), 2.85 (br d, 4H, PhCH₂). MS: 389 (M+1, 100),345 (3.7), 280 (1.8), 120 (6.1).

PROCEDURE 4

Formation of cyclic ureas (XXIIa), (XXIIb) and (XXIIc): ##STR38##

A. Cyclization of SEM ether (XXIa).

Compound (XXIa) (40 g, 71.3 mmol) was dissolved in methylene chloride(200 mL). Carbonyl diimidazole (13.87 g, 85.6 mmol) was dissolved inmethylene chloride (200 mL) in a separate flask. Each solution was thenpumped into dry methylene chloride (6 L) at a rate of 90 mL/h. Themixture was then stirred for 18 h at room temperature under nitrogen.TLC (60/40 ethyl acetate/hexane) showed the reaction was complete. Thesolvent was removed at reduced pressure and residue chromatographed onSiO₂ and eluted with 1-50% ethyl acetate/hexane to afford (XXIIa) as awhite solid (38.82 g, 93%). mp: 75°-76° C. NMR (CDCl₃): δ 7.05-7.4 (m,10H, Ph), 4.6-4.8 (dd, 4H, OCH₂ O), 4.08 (s, 2H, CHOCH₂), 3.5-3.91 (m,8H, NH, CHNH, OCH₂ CH₂), 2.86, (br d, 4H, PhCH₂), 0.8-0.95 (m, 4H,SiCH₂). MS: 587 (M+1, 100).

B. Cyclization of MOM ether (XXIb).

Compound (XXIb) (0.53 g, 1.364 mmol) was dissolved in dry methylenechloride (20 mL). In a separate flask, carbonyl diimidazole (0.265 g,1.64 mmol) was dissolved in methylene chloride (20 mL). To a third flaskcontaining pyridine (0.22 mL, 2.73 mmol) in methylene chloride (100 mL)at room temperature under nitrogen were added the first two solutionsvia syringe pump at a rate of 1.7 mL/h. The solution was stirredovernight at room temperature. TLC (50/50 ethyl acetate/methylenechloride) showed that the reaction was complete. The solution was washedwith 5% HCl (50 mL), NaHCO₃ (50 mL), brine (50 mL), dried over MgSO₄,filtered and evaporated. The residue was chromatographed on SiO₂ andeluted with 50-75% ethyl acetate/methylene chloride to afford (XXIIb) asa colorless gum (198 mg, 35%). NMR (CDCl₃): δ 7.1-7.4 (m, 10H, Ph), 4.65(q, 4H, OCH₂ O), 4.13 (s, 2H, NH), 3.89 (t, 2H, CHNH), 3.59 (s, 2H,CHOCH₂), 3.18 (s, 6H, OCH₃), 2.87 (m, 4H, PhCH₂). MS: 415 (M+1, 100),102 (11).

Synthesis of Dimem DiZ Intermediate (XXc):

DiZ Diol (XIX) 507 g (0.89 mol) was stirred in 4 L of dichloromethane.To the slurry was added N,N-Diisopropylethylamine 780 g (6.05 mol) inone portion at room temperature followed by the dropwise addition of2-methoxyethoxymethyl choride 500 g (4 mol) (1 hour addition,exothermic). Heated the solution at reflux for 12 hours. TLC (10:1:10EtOAc:EtOH:Hexanes, Rf=0.56) indicated a complete reaction. The solutionwas worked up by quenching with ice water (3 L). Washed thedichloromethane extract with water (2×2 L) and dried over magnesiumsulfate. The filtrate was taken to dryness. The resultant semi-solid wasdissolved in chlorobutane (1 L). Passed the solution through a four inchpad of silica gel to remove most of the intense red color. To thechlorobutane extract was added hexane (2 L) to precipitate the desiredDiZ Dimem intermediate (XXc). Washed the white solid with hexanes(3×350ml). Dried at room temperature. Recovered the desired DiZ Dimemintermediate as a white solid in a yield of 525 g (79% yield). m.p.52°-54° C., 1H NMR(CDCl₃): 2.80(m, 4H)--CH₂ Ph, 3.38(s, 6H)--OCH₃,3.58(m, 8H)--OCH₂ CH₂ O--, 3.80(m, 2H), 4.20(m, 2H), 4.6-5.2 (m, 10H)NH,H₂ CCO₂, --OCH₂ O--, 7.25(m, 20H)C₆ H₅

Synthesis of Cyclic Urea Intermediate (XXIIc):

DiZ Dimem (XXc) 20 g (26.8mmol) was dissolved in 200 ml oftetrahydrofuran. To the solution was added 2 g of 10% Palladium onCarbon and the suspension stirred for 7 hours under hydrogen(1 atm). TLC(10:1:10 EtOAc:EtOH:Hex, Rf=0.05) indicated a complete reaction. Thesuspension was filtered through a bed of Celite to remove the catalyst.Washed the Celite bed with 150 ml of tetrahydrofuran. Transferred theTHF solution to a 500 ml round bottom flask. To the THF solution wasadded 5.5 g (33.3mmol) 1,1'-Carbonyldiimidazole in several portions as asolid. Stirred at room temperature for 12 hrs. TLC (10:1:10EtOAc:EtOH:Hex, Rf=0.26) indicated a complete reaction. The mixture wasworked up by quenching with ice-cold 0.5N HCl (150 ml) and extractingwith diethyl ether (2×50 ml). The organic extract was washed with water(2×100 ml) and dried over magnesium sulfate. The filtrate was taken todryness. The residue was purified on silica gel(200 g; 1:1 EtOAc:Hexfollowed by 10:1:10 EtOAc:EtOH:Hex) to provide 10.2 g (75.7% yield overtwo steps) of the desired cyclic urea intermediate (XXIIc) as acolorless oil. 1H NMR(CDCl₃): 2.90(m, 4H)--CH₂ Ph, 3.36(s, 6H)--OCH₃,3.40(m, 8H)--OCH₂ CH₂ O--, 3.60(m, 2H), 3.90(t, 2H), 4.10(s, 2H)NH,4.80(q, 4H)--OCH₂ O--, 7.30(m, 10H)C₆ H₅

PROCEDURE 5

General alkylation/hydrolysis procedure:

Compound (XXIIa) (1 mmol) in dry DMF (5 mL) was added to a flaskcontaining sodium hydride (10 mmol, that had been washed with hexane,3×20 mL) in DMF (5 mL). The solution was stirred at room temperatureunder nitrogen for 5 min. Evolution of hydrogen gas was observed. Theappropriate alkyl bromide (5 mmol) was added and the solution wasstirred at room temperature under nitrogen for 1 h. Hindered alkylbromides required heating at 40°-70° C. for up to 5 h. TLC (40/60 ethylacetate/hexane) was used to ensure that no starting material remained.The solution was quenched with methanol (1 mL), partitioned betweenether (60 mL) and water (50 mL) and the organic layer was removed. Theaqueous layer was washed with ether (50 mL), the organic layers combinedand washed with water (4×30 mL), brine (30 mL), dried over MgSO₄,filtered and evaporated. In cases where the alkyl bromide containedbasic nitrogen, 1N NaOH was used in place of water.

The crude product was hydrolyzed directly in methanol (10 mL) and 4NHCl/dioxane (5 mL) for up to 16 h at room temperature. The solution wasevaporated and chromatographed directly on SiO₂ to afford thebis-alkylated cyclic ureas. Where nitrogen was present, the solutionswere first basified with 1N NaOH and extracted with ethyl acetate, driedover MgSO₄, filtered, evaporated and chromatographed. Hydrolysis canalso be carried out using saturated hydrogen chloride in methanol withshorter reaction times.

Hydrolysis of (XXIIb) under the same conditions gave 67% yield of theN,N-unsubstituted cyclic urea Example 1A, mp 170°-174° C.

Example 1G ##STR39##

The experimental procedure is similar to the synthesis of Example 1E.The isomer, (2R,3R,4R,5R)-2,5-diamino-1,6-diphenyl-3,4-hexanediol,needed for the synthesis was isolated from the vanadium trichloridecoupling reaction, as described in copending commonly assigned patentapplication Jadhav et al. U.S. Ser. No. 07/714,042, filed May 31, 1991(see Procedure 1 above).

Example 1G: ¹³ C NMR (CDCl₃): (75.48 MHz) 37.387, 51.51, 65.136, 72.779,118.649, 126.540, 128.409, 129.714, 134.618, 137.757, 162.705.

Synthesis of Monoalkyl Cyclic Urea:

The intermediate from previous step 2 g(4 mmol) was dissolved in 25 mltoluene and placed in a 100 ml round bottom flask. To the solution wasadded 85% KOH 0.82 g(12 mmol) and polyethylene glycol (M.W.=1000) 0.20g. With a Dean Stark trap in place the mixture was refluxed for 4 hoursuntil the theoretical amount of water(0.20 ml) was collected. Cooled toroom temperature and added (bromomethyl)cyclopropane 1.78 g(13.2 mmol).Stirred at 75° C. for 17 hours. TLC(10:1:10 EtOAc:EtOH:Hex, Rf=0.52)indicated that the reaction was complete. Worked up by quenching withaqueous ammonium chloride(50 ml) and extracting with ethyl acetate

Examples 1A-1Z, 1AA-1AZ, and 1BA-1BD

The compounds listed in Table 1a (Examples 1A-1Z, 1AA-1AZ, and 1BA-1BD)were synthesized using the above-described procedures.

                                      TABLE 1a                                    __________________________________________________________________________     ##STR40##                                                                         Stereo-                                                                  Example                                                                            isomer                                                                   Number                                                                             (2,3,4,5)                                                                          R.sup.22      R.sup.23            Ki                                __________________________________________________________________________    1A   RSSR H             H                   +                                 1B   SRRS H             H                   +                                 1C   RSSR CH.sub.2 CHCH.sub.2                                                                         CH.sub.2 CHCH.sub.2 +++                               1D   SRRS CH.sub.2 CHCH.sub.2                                                                         CH.sub.2 CHCH.sub.2 +                                 1E   SSSS H             H                   +                                 1F   RRSR CH.sub.2 CHCH.sub.2                                                                         CH.sub.2 CHCH.sub.2                                   1G   RRRR CH.sub.2 CHCH.sub.2                                                                         CH.sub.2 CHCH.sub.2 ++                                1H   SSSS CH.sub.2 CHCH.sub.2                                                                         CH.sub.2 CHCH.sub.2 +                                 1I   SRRS CH.sub.2 Ph   CH.sub.2 Ph         +                                 1J   SRRS (CH.sub.2).sub.2 O(CH.sub.2).sub.2 OMe                                                      (CH.sub.2).sub.2 O(CH.sub.2).sub.2 OMe                                                            +                                 1K   SRRS 1-geranyl     1-geranyl           +                                 1L   SRRS CH.sub.2 CH.sub.2 OH                                                                        CH.sub.2 CH.sub.2 NHCH(CH(CH.sub.3).sub.2)C(O)O-be                            nzyl                +                                 1M   SRRS CH.sub.2 CH.sub.2 (CH.sub.2 CH.sub.2 O).sub.2 OCH.sub.3                                     CH.sub.2 CH.sub.2 (CH.sub.2 CH.sub.2 O).sub.2                                 OCH.sub.3           +                                 1N   SRRS 3,7-dimethyl-1-octyl                                                                        3,7-dimtethyl-1-octyl                                                                             ++                                1O   RSSR CH.sub.3 OCH.sub.2 CH.sub.2 OCH.sub.2 CH2                                                   CH.sub.3 OCH.sub.2 CH.sub.2 OCH.sub.2 CH2                                                         +                                 1P   RSSR 3,7-dimethyl-1-octyl                                                                        3,7-dimethyl-1-octyl                                                                              ++                                1Q   RSSR 3,7-dimethyl-l-octyl                                                                        H                   ++                                1R   RSSR CH.sub.3 (OCH.sub.2 CH.sub.2).sub.3                                                         H                   +                                 1S   RSSR CH.sub.3 (OCH.sub.2 CH.sub.2).sub.3                                                         CH.sub.3 (OCH.sub.2 CH.sub.2).sub.3                   1T   RSSR HOCH.sub.2 CH.sub.2                                                                         CH.sub.2 CH.sub.2 NHCH(CH(CH.sub.3).sub.2)C(O)O-be                            nzyl                ++                                1U   SRRS CH.sub.2 CH.sub.2 NHCH(CH(CH.sub.3).sub.2)                                                  CH.sub.2 CH.sub.2 NHCH(CH(CH.sub.3).sub.2)                                                        +                                           C(O) O-benzyl C(O) O-benzyl                                         1V   RSSR propyl        propyl              +++                               1W   RSSR methyl        methyl              +                                 1X   RSSR cyclopropyl-methyl                                                                          cyclopropyl-methyl  +++                               1Y   RSSR n-hexyl       n-hexyl             +++                               1Z   RSSR n-butyl       n-butyl             +++                               1AA  RSSR N-morpholinoethyl                                                                           N-morpholinoethyl   +                                 1AB  RSSR n-heptyl      n-heptyl            ++                                1AC  RSSR CH.sub.2 CHC(CH.sub.3).sub.2                                                                CH.sub.2 CHC(CH.sub.3).sub.2                                                                      +++                               1AD  RSSR ethyl         ethyl               ++                                1AE  RSSR CH.sub.2 CHC(CH.sub.3).sub.2                                                                H                   +++                               1AF  RSSR propyl        propyl              +++                               1AG  RSSR CH.sub.3      CH.sub.3            +                                 1AH  RSSR i-pentyl      i-pentyl            +++                               1AI  RSSR 4-pyridylmethyl                                                                             4-pyridylmethyl     ++                                1AJ  RSSR 2-methallyl   2-methallyl         +++                               1AK  RSSR n-pentyl      n-pentyl            +++                               1AL  RSSR i-octyl       i-octyl             ++                                1AM  RSSR i-hexyl       i-hexyl             +++                               1AN  RSSR i-heptyl      i-heptyl            ++                                1AO  RSSR i-butyl       i-butyl             ++                                1AP  RSSR 3-propargyl   3-propargyl         ++                                1AQ  RSSR benzyl        benzyl              +++                               1AR  RSSR 2-pyridylmethyl                                                                             2-pyridylmethyl     ++                                1AS  RSSR phenylpropyl  phenylpropyl        ++                                1AT  RSSR allyl         isoprenyl           +++                               1AU  RSSR 1-cinnamyl    1-cinnamyl                                            1AV       methyl        cyclopropyl-methyl  +++                               1AW  RSSR allyl         cyclopropyl-methyl  +++                               1AX       CH.sub.2 CH.sub.2 N(CH.sub.2).sub.2                                                         allyl                                                 1AY  RSSR methyl        benzyl              ++                                1AZ       N-pyrrolylethyl                                                                             N-pyrrolylethyl                                       1BA                                                                                      ##STR41##                                                                                   ##STR42##                                            1BB       2-furylmethyl 2-furylmethyl                                         1BC       CH.sub.2 CH.sub.2 OCH (CH.sub.2).sub.2                                                      CH.sub.2 CH.sub.2 OCH (CH.sub.2).sub.2                1BD  RSSR isoprenyl     methyl              ++                                __________________________________________________________________________

The K_(i) values in Table 1 were determined using the assay conditionsdescribed below under HIV Protease Inhibtion Assay. The Ki values areindicated as follows: +++=<10 nM; ++=10 nM to 1 μM; +=>1 mM.

Listed below are physical data for representative compounds of theinvention.

Example 1W: mp 170°-174° C. (67% yield). MS: 355 (M+1, 100). NMR (CDCl₃)δ 7.1-7.35(m, 10H, Ph), 4.03(s,2H,CHOH), 3.5(d, 2H, NCH), 2.8-3.1(m, 6H,PhCH₂, OH), 2.58(s, 6H, NH₃).

Example 1AD: mp 214°-215° C. MS: 383(M+1,100). NMR (CDCl₃) δ 7.1-7.35(m, 10H, Ph), 3.95 (s, 2H, CHOH), 3.5 (d, 2H, NCH), 2.8-3.1 (m, 4H,PhCH₂, OH), 2.7 (br s, 2H, OH), 2.3 (m,2H, NCH), 0.95(t, 6H, CH₃).

Example 1AF: mp 180°-182° C. MS: 411 (M+1,100). NMR (CDCl₃) δ7.05-7.3(m, 10H, Ph), 4.0(s, 2H, CHOH), 3.68(m,2H, NCH₂), 3.52(d, 2H,NCH), 3.05(m, 4H, PhCH₂), 2.1(m, 2H, NCH₂), 1.6 (s, 2H, OH), 1.4 (m, 4H,MeCH₂), 0.79(t, 6H, CH₃).

Example 1Z: HRMS: Calc. 439.2960. Found: 439.2959.

Example 1AK: mp 125°-127° C. MS: 467(M+1, 100). NMR(CDCl₃) δ7.15-7.35(m, 10H, Ph), 3.95(s, 2H, CHOH), 3.68(m, 2H, NCH₂),3.55(d, 2H,NCH), 2.9-3.15(m, 4H, PhCH₂), 2.75(s, 2H, OH), 2.18(m, 2H,NCH₂), >8-1.45(m, complex, pentyl).

Example 1Y: mp 110°-112° C. MS: 495(M+1,100). NMR(CDCl₃) δ 7.1-7.35(m,10H, Ph), 4.0(s, 2H, CHOH), 3.65(m, 2H, NCH--H), 3.52(d, 2H, NCH),2.8-3.2(m,4H,PhCH₂), 2.15(m,2H, OH), 0.9-1.45(m, 11H, hexyl).

Example 1AB: mp 100°-101° C. MS: 523(M+1,100). NMR(CDCl₃) δ 7.1-7.35(m,10H, Ph), 3.95(s, 2H, CHOH), 3.65(m, 2H, NCH--H), 3.5(d, 2H, NCH),2.9-3.1(m, 4H, PhCH₂), 2.6(s, 2H, OH), 2.15(m, 2H, NCH), 0.8-1.4(m,complex, heptyl).

Example 1I: MS: 507(M+1,100). NMR(CDCl₃) δ 7.05-7.4(m, 20H, Ph), 4.91(d,4H, PhCH₂ N), 3.5-3.65(m, 4H, NCH, CHOH), 3.05(m, 4H, PhCH₂), 2.35(br s,2H, OH).

Example 5i (R²² and R²³ =allyl; R²⁰ and R²¹ =C(═O)CH₃): mp 164°-166° C.MS: 407(M+1,100). NMR(CDCl₃) δ 7.1-7.4(m, 10H, Ph), 5.65(m, 2H, CH₂ CH),5.01(m, 4H, CH₂ CH), 4.26(m, 4H, NCH₂), 3.91(s, 2H, CHOH), 3.59(d, 2H,CHN), 3.1(m, 4H, PhCH₂), 2.7(m, 2H, CHCH₂), 2.41(s, 2H, OH).

Example 1AO: MS 439(M+1,100). NMR(CDCl₃) δ 7.15-7.35(m, 10H, Ph),4.05(s, 2H, CHOH), 3.7(m,2H, NCH₂), 3.55(d, 2H, NCH), 3.0-3.2(m, 4H,PhCH₂), 2.65(s, 2H, OH), 1.78(m, 2H, NCH), 1.6(s, 2H, CH₂ CH), .82(d,12H, CHMe₂).

Example 1AH: mp 194°-195° C. MS: 467(M+1,100). NMR(CDCl₃) δ 7.15-7.35(m,10H, Ph), 3.95(s, 2H, CHOH), 3.65(m, 2H, NCH), 3.49(d, 2H, NCH),2.9-3.1(m, 4H, PhCH₂), 2.61(s, 2H, OH), 2.2(m, 2H, NCH), 1.1-1.5(m,complex), 0.9(m, 12H, CHMe₂).

Example 1AM: mp 120°-122° C. MS: 495(M+1,100). NMR(CDCl₃) δ 7.1-7.35(m,10H, Ph), 3.95(s, 2H, NCH), 3.45-3.7(m, 4H, NCH₂, NCH), 2.9-3.2(m, 4H,PhCH₂), 2.1(m, 2H, NCH₂), 0.78-1.45(m, complex, hexyl).

Example 1AN: mp 105°-107° C. MS: 523(M+1,100). NMR(CDCl₃) δ 7.18-7.31(m,10H, Ph), 3.95(s, 2H, CHOH), 3.7(m, 2H, NCH₂), 3.56(d, 2H, NCH),2.9-3.15(m, 4H, PhCH₂), 2.18(m, 2H, NCH₂), 0.9-1.45(m, complex, hexyl).

Example 1AL: mp 144°-145° C. MS: 551(M+1,100). NMR(CDCl₃) δ7.15-7.35(m,10H, Ph), 3.95(s, 2H, CHOH), 3.65(m, 2H, NCH₂), 3.55(d, 2H,NCH), 2.9-3.15(m, 6H, PhCH₂, OH), 2.15(m, 2H, NCH₂), 0.9-1.5(m, complex,heptyl).

Example 1AC: mp 160°-163° C. MS: 463(M+1,100). NMR(CDCl₃) δ 7.15-7.35(m,10H, Ph), 5.06(br t, 2H, NCH₂ CH), 4.1(dd, 2H, NCH₂), 3.9(s, 2H, CHOH),3.5(d, 2H, NCH), 2.8-3.1(m, 4H, PhCH₂), 1.65(s, 6H, CHCHH₃), 1.38(s, 6H,CHCH₃).

Example 1AJ: mp 205°-207° C. MS: 435(M+1,100). NMR(CDCl₃) δ 7.1-7.35(m,10H, Ph), 4.85(s, 2H, C═CH), 4.58(s, 2H, C═CH), 4.28(d, 2H, NCH₂),3.95(s, 2H, CHOH), 3.7(br d, 2H, CHOH), 2.9-3.2(m, 4H, PhCH₂), 2.5(d,2H, NCH₂), 1.75(s, 6H, CH₃)

Example 1AI: MS: 509(M+1,100). NMR(CDCl₃) δ 7.0-8.4(m, 18H, Ph, pyr.),4.8-5.0(m, 4H, NCH₂), 3.7(s, 2H, CHOH), 3.5(d, 2H, NCH), 2.9-3.2(m, 8H,PhCH₂, pyrCH₂).

Example 1AP: mp 198°-200° C. MS: 403(M+1,100). NMR(CDCl₃) δ 7.2-7.35(m,10H, Ph), 4.5(s, 2H, CCH), 4.42(s, 2H, NCH), 4.1(s, 2H, CHOH), 3.8(d,2H, NCH), 2.9-3.2(m, 4H, PhCH₂), 2.7-2.85(m, 4H, NCH₂).

Example 10: mp 105°-106° C. MS: 531(M+1,100). NMR(CDCl₃) δ 7.1-7.35(m,10H, Ph), 3.0-4.15(m, complex), 2.25(m, 2H, OH).

Example 1S: MS: 619(M+1,100). NMR(CDCl₃) δ 7.18-7.3(m, 1OH, Ph),3.0-4.2(m, complex), 2.25(m,2H,OH).

Example 1P: mp 80°-82° C. MS: 607(M+1,100), 257(9.6). NMR(CDCl₃) δ7.05-7.35(m,10H, Ph), 3.95(s, 2H, CHOH), 3.4-3.75(m, 4H, NCH, NCH₂),2.9-3.15(m, 4H, PhCH₂), 2.1(m,2H, OH), 0.85-1.6(m, complex).

Example 1AA: mp 70°-75° C. MS: 553(M+1,100). NMR(CDCl₃) δ 7.05-7.4(m,10H, Ph), 3.4-4.25(m, complex), 2.9-3.15(m, 4H, PhCH₂), 2.2-2.8(m,complex).

Example 1X: mp 210°-212° C. MS: 435(M+1,100). NMR(CDCl₃) δ 7.18-7.35(m,10H, Ph), 4.06(s, 2H, CHOH), 3.68(br d, 2H, NCH), 3.55(q, 2H, NCHCH),3.1(m, 4H, PhCH₂), 2.55(s, 2H, OH), 2.05(q, 2H, CHCH), 0.9(m, 2H, NCH₂CH), 0.42(m, 4H, --CH₂ --), 0.008(m, 4H, --CH₂ --)

    ______________________________________                                        Example Number      MS (M + 1)                                                ______________________________________                                        1B                  327.9                                                     1D                  406.5                                                     1H                  407                                                       1J                  531                                                       1K                  463                                                       1L                  604.5                                                     1M                  619                                                       1N                  607                                                       1O                  467                                                       1R                  473                                                       1T                  604                                                       1U                  793                                                       1V                  411                                                       1AE                 395                                                       1AG                 355                                                       1AS                 563                                                       1AT                 435                                                       1BD                 409                                                       1AQ                 507.26                                                    1AU                 559.29                                                    1BE                 457.2                                                     1BF                 557.5                                                     1BG                 593.4                                                     Example 1AR:        mp 85-87° C.                                       Example 1C:         mp 164-166° C.                                     Example 1A:         mp 170-174° C.                                     ______________________________________                                    

Using the above-described techniques or variations thereon appreciatedby those of skill in the art of chemical synthesis, the compounds ofTables 1b can be prepared.

                                      TABLE 1b                                    __________________________________________________________________________     ##STR43##                                                                    Example                                                                       Number                                                                              R22     R23     R4      R7                                              __________________________________________________________________________    1BE   methyl  phenylmethyl                                                                          4-F-    4-F-                                                                  phenylmethyl                                                                          phenylmethyl                                    1BF   allyl   cyclopropyl-                                                                          4-F-    4-F-                                                          methyl  phenylmethyl                                                                          phenylmethyl                                    1BG   allyl   cyclopropyl-                                                                          4-Cl-   4-Cl-                                                         methyl  phenylmethyl                                                                          phenylmethyl                                    1BH   allyl   cyclopropyl-                                                                          1-pyrolyl-                                                                            1-pyrolyl-                                                    methyl  methyl  methyl                                          1BI   allyl   ethyl   4-F-    4-F-                                                                  phenylmethyl                                                                          phenylmethyl                                    1BJ   isoprenyl                                                                             isoprenyl                                                                             1-pyrrolyl-                                                                           1-pyrrolyl-                                                           methyl  methyl                                          1BK   n-butyl n-butyl 4-hydroxy-                                                                            4-hydroxy-                                                            benzyl  benzyl                                          1BL   N-2-    cyclopropyl-                                                                          benzyl  1-pyrazolyl-                                          acetoamido-3-                                                                         methyl          methyl                                                methyl-butane                                                           1BM   benzyl  cyclopropyl-                                                                          benzyl  1-pyrazolyl-                                                  methyl          methyl                                          1BN   cyclopropyl-                                                                          cyclopropyl-                                                                          4-phenyl-                                                                             1-pyrrolyl-                                           methyl  methyl  benzyl  methyl                                          1BO   cyclopropyl-                                                                          cyclopropyl-                                                                          benzyl  1-imidazolyl-                                         methyl  methyl          methyl                                          1BP   cyclopropyl-                                                                          cyclopropyl-                                                                          benzyl  1-pyrrolyl-                                           methyl  methyl          methyl                                          1BQ   n-butyl cyclopropyl-                                                                          benzyl  1-pyrrolyl-                                                   methyl          methyl                                          1BR   cyclopropyl-                                                                          cyclopropyl-                                                                          benzyl  1-pyrazolyl-                                          methyl  methyl          methyl                                          1BR1  H       cyclopropyl-                                                                          1-pyrrolyl-                                                                           1-pyrrolyl-                                                   methyl  methyl  methyl                                          1BR2  allyl   allyl   benzyl  4-pyridinyl-                                                                  methyl                                          1BR3  N-butyl cyclopropyl-                                                                          benzyl  4-pyridinyl-                                                  methyl          methyl                                          __________________________________________________________________________

Synthesis of Cyclic Guanidines

Cyclic guanidine compounds of the invention wherein W=NH(C═N--CN)NH,differ from the cyclic urea compounds of the invention whereinW=NH(C═O)NH. Described below are representative methods for thepreparation of cyclic quanidine compounds of the invention.

SYNTHESIS OF CYCLIC GUANIDINES ##STR44##

The structures of the Examples below are shown in Table 1c.

Example 1BS

SYNTHESIS OF INTERMEDIATE A: Diamino Disem 561 mg(1 mmol) was dissolvedin 2 ml pyridine and to this solution was added 175 mg(1.2 mmol)Dimethyl N-cyanodithioiminocarbonate. The contents were refluxed in a125° C. oil bath for 2 hours. (Caution: Methyl mercaptan is a by-productand the reaction should be vented to a Clorox scrubber). TLC(1:2EtOAc:Hexane Rf=0.4) indicated a complete reaction. The reaction wasdiluted with 100 ml dichloromethane. The organic layer was washed with1N HCL(2×25 ml) followed by sat. sodium bicarbonate solution(25 ml). Itwas separated and dried over magnesium sulfate and the filtrate taken todryness. The residue was purified on SiO₂ gel(55 g; using 1:3 followedby 1:2 EtOAc:Hexane) to provide 372 mg(60.9% yield) of the desiredintermediate A as a colorless oil.

SYNTHESIS OF INTERMEDIATE B: Intermediate A 305 mg(0.5 mmol) wasdissolved in 2 ml dimethylformamide and to this solution, cooled in a 0°C. ice bath, was added NaH(60% in oil) 80 mg(2 mmol) slowly. Thecontents were stirred at room temperature for 30 minutes. The mixturewas cooled in a 0° C. ice bath and (bromomethyl)cyclopropane 0.19 ml(2mmol) was added via syringe and stirred at room temperature for 18hours. TLC(1:4 EtOAc:Hexane R_(f) =0.31) indicated a complete reaction.The reaction was worked up by diluting with water(50 ml) and extractingwith diethylether (2×25 ml). The organic layer was dried over magnesiumsulfate and the filtrate taken to dryness. The residue was purified onSiO₂ gel(33 g; 1:5 followed by 1:4 EtOAc:Hexane) to provide 243 mg(67.6%yield) of the desired intermediate B as a colorless oil.

SYNTHESIS OF EXAMPLE 1BS: Intermediate B 110 mg (0.153 mmol) was placedin a 10 ml R.B. Flask and cooled in a 0° C. ice bath. To the flask wasadded 4M HCl in dioxane 1ml (4 mmol) and the mixture stirred at roomtemperature for 15 minutes. TLC(1:1 EtOAc:Hexane Rf=0.15) indicated acomplete reaction. The mixture was worked up by quenching in sat. sodiumbicarbonate(25 ml) and extracting with dichloromethane (2×25 ml). Theorganic extracts were dried over magnesium sulfate and the filtratedtaken to dryness. The residue was purified on SiO2 gel(33 g; 1:1EtOAc:Hexane followed by 10:1:10 EtOAc:EtOH:Hexane) to provide 27mg(38.5% yield) of the desired Q8239 as a white solid. m.p.211.2° C.

Example 1BT

SYNTHESIS OF INTERMEDIATE C: Intermediate A 1.515 g(2.48 mmol) wasdissolved in 7.5 ml dimethylformamide and to this solution, cooled in a0° C. ice bath, was added NaH(60% in oil) 397 mg(9.92 mmol) slowly. Thecontents were stirred at room temperature for 30 minutes. The mixturewas cooled in a 0° C. ice bath and p-benzyloxybenzyl chloride 2.308g(9.92 mmol) was added as a solid and the mixture stirred at roomtemperature for 18 hours. TLC(1:4 EtOAc:Hexane R_(f) =0.31) indicated acomplete reaction. The reaction was worked up by diluting with water(100ml) and extracting with diethylether (2×50 ml). The organic layer wasdried over magnesium sulfate and the filtrate taken to dryness. Theresidue was purified on SiO₂ gel(130 g; 1:4 followed by 1:3EtOAc:Hexane)to provide 2.068 g(83.1% yield) of the desired intermediateC as a colorless foam.

SYNTHESIS OF EXAMPLE 1BT: Intermediate C 1.928 g (1.92 mmol) was placedin a 100 ml R.B. flask and cooled in a 0° C. ice bath. To the flask wasadded 4M HCl in dioxane 15 ml (60 mmol) and the mixture stirred at roomtemperature for 15 minutes. TLC(1:1 EtOAc:Hexane Rf=0.25) indicated acomplete reaction. The mixture was worked up by quenching in 0.5N sodiumhydroxide solution(100 ml) and washing with sat.sodium bicarbonate(50ml) and extracting with dichloromethane (3×50 ml). The organic extractswere dried over magnesium sulfate and the filtrate taken to dryness. Theresidue was purified on SiO₂ gel(130 g; 1:1 EtOAc:Hexane) to provide1.284 g(89.9% yield) of the desired product as a white solid. m.p.90.1°C.

Example 1BU

SYNTHESIS OF EXAMPLE 1BU: Example Number 1BT 1.161 g(1.56 mmol) wasdissolved in 15 ml of ethanol. To the mixture was added 1.1 g of 5%Palladium on Carbon and the suspension stirred for 18 hours underhydrogen(1 atm). TLC indicated an incomplete reaction. The mixture wastreated with 1.1 g of 10% Palladium Hydroxide on Carbon and stirred for2 hours under hydrogen(1 atm). TLC(10:1:10 EtOAc:Hexane R_(f) =0.31)indicated a complete reaction. The suspension was filtered through acelite pad and the filtrate taken to dryness. The residue was purifiedon SiO₂ gel(130 g; 10:1:10 followed by 10:2:10 EtOAc:EtOH:Hexane) toprovide 458 mg(52.2% yield) of the desired product as a white solid.m.p.103.3° C.

                                      TABLE 1c                                    __________________________________________________________________________     ##STR45##                                                                    Example                  M + H                                                Number                                                                              R            Ki IC.sub.90                                                                        (M + NH.sub.4)                                                                      m.p. (°C.)                              __________________________________________________________________________    1BS   cyclopropylmethyl                                                                          ++ +++                                                                              459   211.2                                          1BT   CH.sub.2 (C.sub.6 H.sub.4)-p-OCH.sub.2 C.sub.6 H.sub.5                                     ++ +  743   90.1                                           1BU   CH.sub.2 (C.sub.6 H.sub.4)-p-OH                                                            +++                                                                              +++                                                                              563   103.3                                          1BV   cyclopentylmethyl                                                                          +++                                                                              +++                                                                              515   99.7                                           1BW   allyl        ++ ++ 431   70.2                                           1BX   n-butyl      +++                                                                              +++                                                                              463   58.3                                           1BY   Beta-napthylmethyl                                                                         ++ +  631   111.1                                          1BZ   benzyl       ++ +++                                                                              531   94.0                                           1CA   CH.sub.2 (C.sub.6 H.sub.4)-m-OCH.sub.2 C.sub.6 H.sub.5                                     ++ +  743   75.2                                           1CB   p-nitrobenzyl                                                                              ++ ++ 621   130.3                                          1CC   rn-nitrobenzyl           114                                            1CD   CH.sub.2 (C.sub.6 H.sub.4)-m-OH                                                            +++                                                                              +++                                                                              563   124                                            1CE   p-aminobenzyl                                                                              ++ +++                                                                              561   226.3                                          1CF   m-aminobenzyl                                                                              +++                                                                              +++                                                                              561   114.4                                          1CG   p-nitrilobenzyl                                                                            ++ +++                                                                              581                                                  1CH   m-nitrilobenzyl                                                                            ++ +++                                                                              (598) 108.5                                          1CI   dimethylallyl                                                                              ++ +++                                                                              487   72.9                                           1CJ   cyclohexylmethyl                                                                           +++                                                                              +++                                                                              543   96.4                                           1CK   cyclobutylmethyl                                                                           +++                                                                              +++                                                                              487   235.5                                          1CL   propyl       ++ +++                                                                              435   216.6                                          1CM   3-methyl-1-butyl                                                                           ++ +++                                                                              491   76.1                                           1CN   CH.sub.2 (C.sub.6 H.sub.4)-p-CH.sub.2 OH                                                   ++ +++                                                                              591   100.9                                          1CO   CH.sub.2 (C.sub.6 H.sub.4)-m-CH.sub.2 OH                                                   +++                                                                              +++                                                                              591   193.8                                          1CP   CH.sub.2 (C.sub.6 H.sub.4)-m-CHO                                                           +++                                                                              +++                                                                              587                                                  1CQ   CH.sub.2 (C.sub.6 H.sub.4)-m-CHNOH                                                         +++                                                                              +++                                                                              617   121.2                                          __________________________________________________________________________

The structures of the Examples below are shown in Tables 1d and 1e.

Example 7F

A solution of Example 1X (120 mg, 0.27 mmol) in methylene chloride (25mL) was cooled in an ice bath at 0° C. and treated with triethylamine(110 mg, 1.1 mmol). Then a solution of thionyl chloride (150 mg, 1.3mmol) in methylene chloride (10 mL) was added dropwise. The mixture wasstirred for 10 minutes and then washed with sat'd NaHCO₃ (aq), brine,and dried over MgSO₄. The solution is filtered and the solvent removedon a rotary evaporator and the resulting residue is HPLC chromatographedon silica gel (50% EtOAc/Hexanes) to give 100 mg of a white foam. HRMScalculated for C₂₇ H₃₂ N₂ O₄ S: 481.2161; found: 481.2152.

Example 7G

A solution of Example 1X (120 mg, 0.27 mmol) in methylene chloride (25mL) was cooled in an ice bath at 0° C. and treated with triethylamine(80 mg, 0.8 mmol). Then a solution of trichloromethyl chloroformate(DIPHOSGENE) (53 mg, 0.27 mmol) in methylene chloride (5 mL) was addeddropwise. The mixture was stirred for 60 minutes and then washed withsat'd NaHCO₃ (aq), brine, and dried over MgSO₄. The solution is filteredand the solvent removed on a rotary evaporator and the resulting residueis chromatographed on silica gel (50% EtOAc/Hexanes) to give 90 mg of awhite foam. MS(NH₃) 461 (M+H)⁺.

Example 7I

A solution of Ex. 1X (500 mg, 1.15 mmol) in THF (25 mL) was treated withthiocarbonyldiimidazole (410 mg, 2.3 mmol) and heated to reflux for 1.5hours. The solvent is removed on a rotary evaporator and the resultingresidue is chromatographed on silica gel (50% EtOAc/Hexanes) to give 320mg of a white solid. MS(NH₃) 477.3(M+H)⁺

Example 7H and 7U

A solution of Example 7I (220 mg, 0.46 mmol) in dry toluene (25 mL) washeated to reflux and treated with Bu₃ SnH (0.4 mL, 1.5 mL) and 20 mg ofAIBN. The mixture was heated at reflux for 2.5 hours. The solvent isremoved on a rotary evaporator and the resulting residue ischromatographed on silica gel (20% EtOAc/Hexanes) to give 70 mg of 7H asa white solid. MS(NH₃) 447.2. (M+H)⁺. A later fraction gave 30 mg ofExample 7U as a white solid. MS 419.2 (M+H)⁺.

Example 7V

A solution of Ex. 1X (112 mg, 0.26 mmol) in methylene chloride (5 mL)was cooled in an ice bath at 0° C. and treated with DAST (110 mg, 1.1mmol). The mixture was stirred for 10 minutes and then washed with sat'dNaHCO₃ (aq), brine, and dried over MgSO₄. The solution is filtered andthe solvent removed on a rotary evaporator and the resulting residue isHPLC chromatographed on silica gel (65% EtOAc/Hexanes) to give 40 mg ofa colorless residue. HRMS calculated for C₂₇ H₃₃ N₂ O₂ F: 437.2604;found: 437.2593.

Example 7O

A solution of Ex. 3U (600 mg, 1.9 mmol) in pyridine (10 mL) is treatedwith methanesulfonyl chloride (170 mg, 1.5 mmol) and stirred at roomtemperature for 3 hours. The mixture is quenched with 5 mL of methanol.The solution is concentrated on a rotary evaporator and the resultingresidue is dissolved in ethyl acetate and then washed with diluteHCl(aq), brine, and dried over MgSO₄. The solution is filtered and thesolvent removed on a rotary evaporator and the resulting residue ischromatographed on silica gel (40% EtOAc/Hexanes) to give Example 7O(420 mg ) as a white solid. MS 685(M+H)⁺.

Example 7Y

A solution of Example 7O (100 mg, 0.15 mmol) in DMF (4 mL) was treatedwith NaN₃ (100 mg, 1.5 mmol) and heated at 80° C. for 2 hrs and thenstirred overnight at 40° C. The solution was diluted with water and theresulting white solid is extracted into ethyl acetate. The organicextract is washed with water, brine, and dried over MgSO₄. The solutionis filtered and the solvent removed on a rotary evaporator and theresulting residue is HPLC. chromatographed on silica gel (50%EtOAc/Hexanes) to give Example 7Y (80 mg ) as a white solid. MS632(M+H)⁺. IR (CHCl₃) 2214 cm⁻¹ for N₃.

Example 7J and 7K

A solution of Ex. 3U (100 mg, 0.165 mmol) in pyridine (3 mL) is treatedwith acetic anhydride (84 mg, 0.824 mmol) and stirred at roomtemperature for 2 hours. The mixture is quenched with 5 mL of methanol.The solution is concentrated on a rotary evaporator and the resultingresidue is dissolved in ethyl acetate and then washed with diluteHCl(aq), brine, and dried over MgSO₄. The solution is filtered and thesolvent removed on a rotary evaporator and the resulting residue is HPLCchromatographed on silica gel (40% EtOAc/Hexanes) to give Example 7J (24mg ) as a white solid. HRMS:(M+H)⁺ calculated for C₄₅ H₄₃ N₂ O₅ :691.317198; found: 691.316252. Also gives as a later fraction Example 7K(27 mg) as a white solid. HRMS: (M+H)+calculated for C₄₃ H₄₁ N₂ O₄ :649.306633; found: 649.304918.

Example 7R

A solution of Ex. 3U (100 mg, 0.165 mmol) in methylene chloride (5 mL)is treated with 2,2dimethoxy propane (174 mg, 1.65 mmol),p-toluenesulfonic acid (10 mg) and stirred at room temperature forovernight. The mixture is diluted with methylene chloride and washedwith saturated NaHCO₃, brine, and dried over MgSO₄. The solution isfiltered and the solvent removed on a rotary evaporator and theresulting residue is HPLC chromatographed on silica gel (50%EtOAc/Hexanes) to give Example 7R (73 mg ) as a white solid. HRMS:(M+H)⁺calculated for C₄₄ H₄₃ N₂ O₃ : 647.327369; found: 647.327531

Example 7P

A solution of Ex. 3U (200 mg, 0.33 mmol) in methylene chloride (5 mL) istreated with oxalyl chloride (249 mg, 2.0 mmol) and stirred at roomtemperature for overnight. The solvent removed on a rotary evaporatorand the resulting residue is HPLC chromatographed on silica gel (50%EtOAc/Hexanes) to give a tan solid. This was recrystallized from CH₂ Cl₂/hexane to give Example 7P (80 mg ) as a white solid. MS: 661.4(M+H)⁺.

Example 7S

A solution of Ex. 3U (100 mg, 0.165 mmol) in methylene chloride (5 mL)is treated with trimethylorthobutyrate (244 mg, 1.65 mmol)p-toluenesulfonic acid (10 mg) and stirred at room temperature for 30minutes. The mixture is diluted with methylene chloride and washed withsaturated NaHCO₃, brine, and dried over MgSO₄. The solution is filteredand the solvent removed on a rotary evaporator and the resulting residueis HPLC. chromatographed on silica gel (50% EtOAc/Hexanes) to give Ex.7S. MS: 691.5(M+H)⁺

Example 7B

A solution of the Di-MEM protected Ex. 1C (550 mg, 0.94 mmol) inpyridine (11 mL) is treated with P₂ S₅ (420 mg, 0.94 mmol) and heated toreflux for 3 hrs. The pyridine is evaporated off on a rotary evaporatorand the residue is taken up in methylene chloride and washed with water,NaHCO₃, and brine. The solution is dried over MgSO₄, filtered and thesolvent removed on a rotary evaporator and the resulting residue ischromatographed on silica gel (40% EtOAc/Hexanes) to give Example 7B(120 mg) as a clear oil. HRMS:(M+H)⁺ calculated for C₂₇ H₃₃ N₂ O₃ S:465.221190; found: 465.220899.

Example 7A

A solution of Example 1C (330 mg, 0.8 mmol) in pyridine (5 mL) istreated with acetic anhydride (160 mg, 1.6 mmol) and stirred at roomtemperature for 4 hours. The mixture is quenched with 5 mL of methanol.The solution is concentrated on a rotary evaporator and the resultingresidue is dissolved in ethyl acetate and then washed with dilute HCl(aq), brine, and dried over MgSO₄. The solution is filtered and thesolvent removed on a rotary evaporator and the resulting residue ischromatographed on silica gel (50% EtOAc/Hex) to give Example 7A (120mg) as a white solid. MS:(CI, NH₃) 449.1 (M+H)⁺.

Example 7W

A solution of example 1C (160 mg, 0.39 mmol) in methylene chloride (5mL) was cooled in an ice bath at 0° C. and treated with DAST (63 mg, 0.4mmol). The mixture was stirred for 10 minutes and then washed with sat'dNaHCO₃ (aq), brine, and dried over MgSO₄. The solution is filtered andthe solvent removed on a rotary evaporator and the resulting residue isHPLC. chromatographed on silica gel (50% EtOAc/Hex) to give 80 mg of acolorless residue. HRMS calculated for C₂₅ H₃₀ N₂ O₂ F: 409.2291; found:409.2291.

Example 7X

A solution of example 3U (100 mg, 0.16 mmol) in methylene chloride (5mL) was cooled in an ice bath at 0° C. and treated with DAST (26 mg,0.16 mmol). The mixture was stirred for 10 minutes and then washed withsat'd NaHCO₃ (aq), brine, and dried over MgSO₄. The solution is filteredand the solvent removed on a rotary evaporator and the resulting residueis HPLC. chromatographed on silica gel (50% EtOAc/Hex) to give 35 mg ofa white foam. HRMS calculated for C₄₁ H₃₈ N₂ O₂ F: 609.2917; found:609.2911.

Example 8A

A solution of example 1X (2.06 g, 4.74 mmol) in methylene chloride wastreated with diisopropylethylamine (1.53 g, 11.8 mmol), MEM-Cl (0.71 g,5.7 mmol) and heated to reflux for 5 hours and let stir overnight at rt.The solution is concentrated on a rotary evaporator the residue is HPLC.chromatographed on silica gel (5% MeOH/CHCl₃) to give 1.3 g of themono-MEM mono-ol intermediate. MS:(CI, NH₃) 523.4(M+H)⁺.

A solution of mono-MEM mono-ol intermediate from above (1.0 g, 1.9 mmol)in THF was treated with triphenylphosphine (1.0 g, 3.8 mmol),diethylazadicarboxylate (DEAD) (0.7 g, 4.0 mmol), and chloroacetic acid(0.4 g, 4.2 mmol). The solution is stirred overnight at rt. The solventis evaporated and the resulting residue is chromatographed on silica gel(50% EtOAc/Hex) to give 0.9 g of the chloroacetate intermediate. MS:(CI,NH₃) 599.3(100%, (M+H)⁺); 600 (39%).

The chloroacetate intermediate (0.9 g, 1.5 mmol) was dissolved in MeOH(15 ml) and treated with NaOH(aq) (4 ml, 1N) and stirred at rt for 15min. The solution was evaporated to dryness and the residue partitionedbetween water and ethyl acetate. The organic layer was washed with waterand brine and then dried over MgSO₄. The solution is the filtered,concentrated and the residue is HPLC. chromatographed on silica gel (85%EtOAc/Hex) to give 400 mg of example 8A. MS:(CI, NH₃) 523.4(M+H)⁺.

Example 7Z

A solution of example 8A (100 mg, 0.2 mmol) in MeOH is cooled in an icebath and treated with HCl .sub.(g) for 20 min and then stirred for anadditional 40 min at 0° C. The solution is then evaporated to dryness atrt and the residue is HPLC. chromatographed on silica gel (80%EtOAc/Hex) to give 48 mg of example 7Z as a white foam. MS:(CI, NH₃)435.2(M+H)⁺

Example 8C

A solution of example 8A (160 mg, 0.3 mmol) in methylene chloride (10ml) is cooled to 0° C. in an ice bath and treated with DAST (50 mg, 0.3mmol). The solution is stirred at rt for 15 min and then quenched withwater. The organic layer is washed with water and brine and dried overMgSO₄. The solution is filtered, the solvent evaporated and the residueHPLC chromatographed on silica gel (50% EtOAc/Hex) to give 100 mg ofexample 8C. MS:(CI, NH₃) 525.4(M+H)⁺

Example8B

A solution of example 8C (70 mg, 0.13 mmol) in MeOH is cooled in an icebath and treated with HCl .sub.(g) for 20 min and then stirred for anadditional 40 min at 0° C. The solution is then evaporated to dryness atrt and the residue is HPLC. chromatographed on silica gel (80%EtOAc/Hex) to give 40 mg of example 8B as a white foam. MS:(CI,NH3)437.3 (M+H)⁺

Example 7AA

To a stirred suspension of 750 mg (1.72 mmol) of the diol (1×) in 35 mLof methylene chloride was added 445 mg (3.45 mmol) ofdiisopropylethylamine and 322 mg (2.59 mmol) of MEM chloride. Afterstirring 5 days the resulting solution was washed with dilute HCl, brineand was dried with anhydrous MgSO₄. The solvent was removed underreduced pressure and the residue was chromatographed on silica gel.Elution with 50% ethyl acetate in hexanes gave 430 mg (48%) of the monoprotected ether (XXVa). MS:523 (M+1,100); NMR (CDCl₃): δ 7.20 (m,10H),4.96 (s,2H), 4.08 (m,1H), 3.90 (m,2H), 3.61 (m,7H), 3.42 (s,3H), 3.13(m,4H), 1.99 (m,2H), 0.88 (m,2H), 0.40 (m,4H), 0.06 (m,4H),

To a stirred solution of 78 mg (0.15 mmol) of Compound (XXVa) in 3 ml ofmethylene chloride was added 60 mg (0.74 mmol) of sodium acetate and 95mg (0.44 mmol) of PCC. The resulting suspension was stirred 3 days andwas diluted with ether and filtered through florisil. The solvent wasremoved under reduced pressure and the residue was chromatographed onsilica gel. Elution with 2.5% methanol in methylene chloride gave 68 mg(885) of example 7AA. MS:521 (M+1,100); NMR (CDCl₃): δ 7.21 (m,10 H),4.90 (d,1H), 4.70 (dd,2H), 4.10 (t,1H), 3.80-3.37 (m,8H), 3.36 (s,3H),3.26-2.82 (m,4H), 2.22 (q,1H), 1.03 (m,2H), 0.51 (m,4H), 0.20 (m,4H),

Oxidation of monoprotected diol: Preparation of (XXVb):

To a stirred solution of 51 mg (0.10 mmol) of example 7AA in 4 mL ofmethanol was added 1 mL of concentrated HCl. The resulting solution wasstirred 5 h and the product was precipitated by adding water. Thesuspension was extracted with methylene chloride and the combinedorganic layers were dried with anhydrous MgSO₄. The solvent was removedunder reduced pressure and the residue was chromatographed on silicagel. Elution with 33% ethyl acetate in hexanes gave 34 mg (80%) of theketol (XXVb). MS:433 (M+1,100); NMR (CDCl₃): δ 7.21 (m,10H), 4.82(m,1H), 4.24 (t,1H), 3.85 (m,1H), 3.74 (d,1H), 3.44 (m,3H), 3.22-2.73(m,4H), 2.27 (q,1H), 1.01 (m,2H), 0.51 (m,4H), 0.20 (m,4H),

Example 7AC

To a stirred solution of 37 mg (0.09 mmol) of the ketol (XXVb) in 4 mLof ethanol and 2 mL of water was added 40 mg (0.48 mmol) ofmethoxylamine hydrochloride. The resulting solution was stirredovernight and the product was precipitated by adding water. Thesuspension was extracted with methylene chloride and the combinedorganic layers were dried with anhydrous MgSO₄. The solvent was removedunder reduced pressure to give 40 mg (100%) of example 7AC. MS: 462(M+1,100); NMR (CDCl₃) δ 7.20 (m,10H), 5.30 (m,2H), 4.80 (t,1H), 4.24(t,1H), 3.77 (m,4H), 3.40 (m,3H), 2.90 (m,4H), 2.25 (dd,1H), 1.03(m,2H), 0.48 (m,4H), 0.23 (m,2H), 0.12 (m,2H).

Example 7AB

By substituting hydroxylamine hydrochloride in the above procedure, thedesired product can be obtained: MS: 448 (M+1,100); NMR (CDCl₃): δ 8.13(s,1H), 7.20 (m,10H), 5.42 (t,1H), 4.83 (t,1H), 3.75 (m,2H), 3.40(m,3H), 2.94 (m,4H), 2.22 (dd,1H), 1.17 (m,1H), 0.90 (m,1H), 0.47(m,4H), 0.23 (m,2H), 0.11 (m,2H).

Example 7AD

To a stirred solution of 98 mg (0.23 mmol) of ketol (XXVb) in 5 mL ofbutanol was added 57 mg (0.71 mmol) of formamidine hydrochloride and 40mg (0.75 mmol) of sodium methoxide. The resulting suspension was stirred30 min and was refluxed overnight. The butanol was removed under reducedpressure and water was added. The suspension was extracted withmethylene chloride and the combined organic layers were dried withanhydrous MgSO₄. The solvent was removed under reduced pressure and theresidue was chromatographed on silica gel. Elution with 25% ethylacetate in hexanes gave 28 mg (28%) of example 7AD. MS:442 (M+1,100);NMR (CDCl₃) δ 7.58 (s,1H), 7.20 (m,10H), 4.55 (m,2H), 3.51 (m,2H), 3.24(m,2H), 3.05 (m,2H), 2.53 (q,1H), 2.27 (q,1H), 0.91 (m,2H), 0.45 (m,4H),0.11 (m,4H).

Examples 7AE and 7AF

To a stirred solution of 65 mg (0.15 mmol) of the diol (1×) in 1 mL ofDMF was added 5.5 mg (0.18 mmol) of 80% sodium hydride. The resultingsuspension was stirred 20 min. and 68 mg (0.48 mmol) of methyl iodidewas added. After stirring overnight, the suspension was quenched withwater, extracted with ethyl acetate, and the combined organic layerswere dried with anhydrous MgSO₄. The solvent was removed under reducedpressure and the residue was chromatographed on silica gel. Elution with25% ethyl acetate in hexanes gave 19 mg (28%) of example 7AE along with25 mg (37%) of Example 7AF.

Example 7AE: MS: 449 (M+1,100); NMR (CDCl₃): δ 7.26 (m,10H), 4.05(dd,1H), 3.84 (m,1H), 3.67 (m,2H), 3.60 (s,3H), 3.53 (m,2H), 3.13(m,3H), 2.90 (m,2H), 1.94 (dt,2H), 0.89 (m,2H), 0.41 (m,4H), 0.04(m,4H),

Example 7AF: MS: 463 (M+1,100); NMR (CDCl₃): δ 7.21 (m,10H), 3.67(m,4H), 3.62 (s,6H), 3.58 (s,2H), 3.10 (m,4H), 1.92 (dd,2H), 0.83(m,2H), 0.41 (m,4H), 0.04 (m,4H).

Examples 7AG and 7AH

By substituting benzyloxymethyl chloride in the above procedure, example7AG and 7AH were obtained.

Example 7AG: MS: 615 (M+1,100); ¹ H NMR (CDCl₃): δ 7.50-7.06 (m,20H),4.88 (ab,4H), 3.92 (s,2H), 3.56 (m,2H), 3.47 (dd,2H), 3.14 (m,4H), 1.88(dd,2H), 0.62 (m,2H), 0.34 (m,4H), 0.05 (m,4H).

Example 7AH: MS: 525 (M+1,100); ¹ H NMR (CDCl₃): δ 7.45-7.10 (m,15H),4.74 (ab,2H), 4.13 (dd,1H), 3.82-3.50 (m,5H), 3.09 (m,4H), 2.76 (s,1H),1.95 (dt,2H), 0.92 (m,2H), 0.40 (m,4H), 0.03 (m,4H).

Examples 7AI and 7AJ

By substituting allyl bromide in the above rocedure, example 7AI and 7AJwere obtained.

Example 7AI: ¹ H NMR (CDCl₃) δ 7.26 (m,10H), 6.05 (m,2H), 5.30 (dd,4H),4.28 (m,2H), 3.76 (s,2H), 3.60 (m,4H), 3.10 (m,4H), 1.93 (dd,2H), 0.86(m,2H), 0.40 (m,4H), 0.01 (m,4H).

Example 7AJ: MS: 475 (M+1,100); ¹ H NMR (CDCl₃) δ 7.27 (m,10H), 6.01(m,1H), 5.32 (dd,2H), 4.34 (dd,1H), 4.18 (dd.1H), 4.66 (m,5H), 3.10(m,4H), 2.82 (s,1H), 1.95 (m,2H), 0.85 (m,2H), 0.40 (m,4H), 0.04 (m,4H)

Example 8E

A solution of Example 5F (500 mg, 0.7 mmol) in methylene chloride (10ml) is cooled to 0° C. in an ice bath and treated with DAST (112 mg, 0.7mmol). The solution is stirred at 0° C. for 15 min and then quenchedwith sat'd NaHCO₃. The organic layer is washed with water and brine anddried over MgSO₄. The solution is filtered, the solvent evaporated andthe residue HPLC chromatographed on silica gel (50% EtOAc/Hex) to give250 mg of example 8E as a white foam. MS:(CI,NH3) 721 (M+H)⁺.

Example 8F

A solution of example 8E (200 mg, 0.28 mmol) in MeOH is cooled in an icebath and treated with gaseous HCl for 20 min and then stirred for anadditional 40 min at 0° C. The solution is then evaporated to dryness atrt and the residue is HPLC. chromatographed on silica gel (5%MeOH/CHCl₃) to give 120 mg of example 8F as a white foam. MS:(CI,NH3)541 (M+H)⁺.

Example 8G (via Alkene Intermediate XXIX)

A solution of Example 7Q (150 mg, 0.22 mmol) in DMF was treated withsodium iodide (160 mg, 1.1 mmol) and heated at 90° C. for 2 hrs. Themixture is cooled to room temperature, diluted with water and theprecipitate is extracted into CH₂ Cl₂. The extract is washed with waterand brine, dried over MgSO₄ and evaporated to give a yellow oil. This isHPLC chromatographed on silica gel (50% EtOAc/Hex) to give 50 mg ofalkene intermediate (XXIX) as a white solid. MS:(CI,NH3) 589 (M+H)⁺.##STR46##

Alkene intermediate (XXIX)

A solution of alkene intermediate (XXIX) (40 mg, 0.07 mmol) in THF wastreated with 20 mg of 10% Pd/C. and hydrogenated in a Parr Hydrogenatorat 50 psi overnight. The catalyst was filtered off and the filtrateconcentrated. The resulting residue was HPLC chromatographed on silicagel (70% EtOAc/Hex) to give 10 mg of Example 8G as a white solid.MS:(CI,NH3) 591.5 (M+H)⁺

Method 2 (As outlined in Scheme 10):

A suspension of Example 3U (2.0 g, 0.0033 mol) in methylene chloride wastreated at room temperature with 2-acetoxyisobutryl bromide (2.09 g,0.01 mol) and stirred for 1 hour until the solution became clear. Thereaction was quenched with a solution of sat'd sodium bicarbonate andthe organic layer was washed with water and brine. The solution wasdried over magnesium sulfate, concentrated and chromatographed on silicagel (30% EtOAc/Hexane elution) to give 1.3 g of the correspondingbromoacetate intermediate as a white solid. MS:(CI,NH3) 713.4 (M+H)⁺.

A solution of the bromo acetate intermediate (0.45 g, 0.63 mmol) inacetic acid was treated with 1 g of zinc dust and stirred at roomtemperature until TLC analysis showed no starting material remained. Themixtured was diluted with ethyl acetate and filtered. The filtrate wasconcentrated and the resulting residue was dissolved in methanol andtreated with 1N aq. NaOH and stirred overnight. The solution wasconcentrated and the residue was dissolved in methylene chloride, washedwith water and brine, dried over magnesium sulfate, and concentrated.The residue was chromatographed on silica gel (50% EtOAc/Hexane elution)to give 170 mg of Example 8G as a white solid. MS:(CI,NH3) 591.5 (M+H)⁺.

Example 8H

Method 1.

A. Synthesis of 6-membered ring cyclic urea (XXX): ##STR47##

The synthesis of the six-membered cyclic urea (XXX) is outlined inScheme 8. A solution of N--Cbz--D-phenylalanineN,O-dimethylhydroxylamide (33.5 g , 0.098 mol) in ether was cooled to 0°C. and treated with 300 mL of a 1M solution of vinyl magnesium bromidein THF. The mixture was stirred for 30 mins and then poured into an icecold solution of 1N HCl (500 mL). The mixture was extracted into etherand the extracts washed with water and brine. The organic layer wasdried over MgSO₄, filtered and concentrated to give the desired vinylketone as a thick, light yellow residue which was used without furtherpurification. MS:(CI,NH3) 310 (77%,(M+H)⁺); 327.1 (100%,(M+NH₄)⁺).

The crude ketone was dissolved in methanol (350 mL) and treated withcerium trichloride heptahydrate (37.2 g, 0.1 mol) and cooled in an icebath. While stirring vigorously sodium borohydride (3.78 g 0.1 mol) wasadded slowly, a small portion at a time, over a period of 30 min. Afterthe addition was complete the mixture was allowed to warm to roomtemperature and stirred for an additional 1 hr. The solvent was removedunder vacuum on a rotorary evaporator and the residue was partitionedbetween 1N HC₁ and methylene chloride. The organic layer was washed withwater, brine, and then dried over MgSO₄, filtered and concentrated togive the desired allylic alcohol as an off-white solid which was usedwithout further purification.

A solution of the crude allylic alcohol and diisopropylethylamine (30 g,0.23 mol) in methylene chloride was cooled in an ice bath and treateddropwise with methanesulfonyl chloride (28 g, 0.24 mol). The solutionwas stirred for 30 mins, then washed sequentially with 1N HCl, water,brine and dried over MgSO₄. The solution was filtered and concentratedto give the crude mesylate as a thick oil. To a flamed-dried flask wasadded copper cyanide (12 g, 0.144 mol) and 100 mL of THF. The flask wascooled to -78° C. under nitrogen atmosphere. A solution ofbenzylmagnesium chloride (360 mL, 2M in THF, 0.72 mol) was added viasyringe and the resulting thick solution was stirred at -60° C. for 20mins and at 0° C. for 30 mins. The solution was then cooled to -78° C.and a solution of the mesylate in 130 mL of THF was added via syringe.The solution was stirred at -60° C. for 45 mins and then poured into amixture of 1N HCl/ice. This was extracted into ethyl acetate and theorganic layer was washed sequentially with NH₄ Cl (aq), NH₄ OH, brine,dried over MgSO₄, filtered and concentrated. The resulting residue ischromatographed on silica gel (hexane, then 10% EtOAc/Hex) to give 11.7g of the desire alkene as a white solid. MS:(CI,NH3) 386.3 (98%,(M+H)⁺); 403.2 (100%, (M+NH₄)⁺).

A solution of the above alkene (11.0 g, 0.029 mol) in methylene chloride(75 mL) was cooled to 0° C. in an ice bath and treated with 60%m-chloroperbenzoic acid (14.0 g, 0.049 mol). The solution was stirred 0°C. for 7 hrs until TLC. analysis showed no starting material remained. Aprecipitate formed during this time. The suspension was diluted withmethylene chloride and washed sequentially with 1N Na₂ S₂ O₃, 1N sodiumhydroxide, water, brine, dried over MgSO₄, filtered and concentrated togive the epoxide as a thick oil which was used without furtherpurification.

To solution of crude epoxide in 80 mL of DMF was added sodium azide (20g , 0.3 mol), ammonium chloride (2.5 g , 0.047 mol) and 20 mL of water.The mixture was heated at 90° C. for 3 hrs and then stirred at rtovernight. The solvent was removed under high vacuum on a rotoraryevaporator and the residue was partitioned between water and methylenechloride. the organic layer was washed with water and brine, dried overMgSO₄, filtered and concentrated to give a residue. This was thenchromatographed on silica gel (20% EtOAc/Hex) to give 7.4 g of the azidealcohol as a white solid. MS:(CI,NH3) 445.0 (25%, (M+H)+); 462.2 (100%,(M+NH₄ -BnOH)⁺).

A solution of the azide alcohol above (7.2 g, 0.016 mol) in methylenechloride was treated with diisopropylethylamine (4.2 g , 0.032 mol) andMEM-Cl (4.0 g 0.032 mol) and heated to reflux overnight (18 hrs). Themixture was concentrated and the residue chromatographed on silica gel(20% EtOAc/Hex-35% EtOAc/Hex) to give 7.7 g of the MEM protected azidoalcohol as a colorless oil. MS:(CI,NH3) 533.2 (100%, (M+H)⁺).

To a solution of MEM protected azido alcohol (5.7 g 0.0107 mol) in ethylacetate was added 2 mL of acetic acid and 1 g of Pearlman's catalyst(10% Pd(OH)₂ on Carbon) and the solution was hydrogenated at 55 psi for22 hrs. The solution was filtered through Celite and the filtrate wasextracted with 1N HCl (organic layer turn orange). The acidic aqueousextract was made basic with 50% NaOH (while cooling in an ice bath) andthe precipitate is extracted into ethyl acetate. The organic layer iswashed with water, brine, dried over MgSO₄, filtered and concentrated togive 2.5 g of the MEM protected diamino alcohol as a colorless oil.MS:(CI,NH3) 373.1 (100%, (M+H)⁺).

To a solution of the MEM protected diamino alcohol (2.5 g 0.0067 mol) inTHF was added 1,1-carbonyldiimidazole (1.1 g, 0.0067 mol) and stirredover night at room temperature. The solution was concentrated and theresidue partitioned between 1N HCl and CH₂ Cl₂. The organic layer iswashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue is HPLC chromatographed on silica gel (5% MeOH/CHCl₃) to give1.2 g of the MEM protected 6-membered ring cyclic urea (XXX) as a whitesolid. MS:(CI,NH3) 399.1 (100%, (M+H)⁺).

B. The MEM protected 6-membered ring cyclic urea (XXX) (100 mg, 0.27mmol) was alkylated with cyclopropylmethylbromide (250 mg , 1.8 mmol)followed by removal of the MEM group, as described in general procedure5, to give after chromatography on HPLC (silica gel, 10% MeOH/CHC₁ ₃) 20mg of Example 8H as a clear, viscous residue. MS:(CI,NH3) 419.4 (100%,(M+H)⁺).

Method 2.

A solution of Example 8A (160 mg, 0.3 mmol) and thiocarbonyldiimidazole(55 mg, 0.3 mmol) in THF was heated to reflux for 4 hrs. The mixture wasevaporated and the residue chromatographed on silica gel (50% EtOAc/Hex)to give 34 mg (0.055 mmol) of the corresponding thiocarbamate. Thethiocarbamate was dissolved in 2 mL of toluene and heated to reflux. Tothe refluxing solution was added tributyltin hydride (32 mg, 0.1 mmol)and 2 mg of AIBN. The mixture was refluxed for 1 hour, concentrated, andthe residue chromatography on HPLC (silica gel, 65% EtOAc/Hex) to give20 mg of clear colorless oil. The oil was dissolved in MeOH, cooled inan ice bath and gaseous HCl was bubbled through the solution for 30mins. The solution was then stirred at room temperature overnight,concentrated and the residue chromatography on HPLC (silica gel, 10%MeOH/CHCl₃) to give 10 mg of Example 8H as a clear, viscous residue.MS:(CI,NH3) 419.2 (100%, (M+H)⁺).

Example 8AA ##STR48##

Compound (XXIIb) (0.85 g) was heated with mixture of acetic acid (9.5mL) and water (0.5 mL) at 85° C. for 4 h. After extraction withdichloromethane, followed by washing the organic extract with saturatedsodium bicarbonate and brine, a mixture was provided which, onseparation by column chromatography, furnished (XXIIb) (TLC. 1:10 ethylacetate/hexane R_(f) =0.4; 0.54 g), the desired mono-alcoholintermediate (TLC 1:10 ethyl acetate/hexane Rf=0.1; 0.13 g), andoverhydrolysed diol (0.05 g).

The above mono-alcohol intermediate 0.25 g (0.466 mmol),triphenylphosphine 183 mg (0.7 mmol), diethylazadicarboxyalte 0.11 mL(0.7 mmol), and chloroacetic acid 66 mg (0.7 mmol) were stirred in 5 mLanhydrous tetrahydrofuran at 0° C. for 15 minutes and then at roomtemperature for 18 h. The excess reagents were quenched with 0.5 mLmethanol and the mixture allowed to stir for 20 minutes. The mixture waspurified by silica gel column chromatography to provide the desiredchloroacetate intermediate with inversion of configuration. ¹³ C. NMR(CDCl₃): (75.48 MHz) -1.373, 14.413, 14.487, 18.253, 25.591, 33.851,35.741, 40.505, 48.824, 49.962, 57.507, 58.234, 66.589, 67.885, 73.179,77.423, 95.454, 117.296, 118.554, 126.588, 126.887, 128.518, 128.610,129.117, 129.199, 129.479, 133.686, 134.168, 136.324, 138.285, 155.698,166.323.

The above chloroacetate intermediate 73 mg (0.12 mmol) in 2 mL drymethanol was treated with 0.25 mL (0.5M) sodium methoxide and stirredfor 30 minutes at room temperature. The contents were then treated with0.3 mL (4% HCl in methanol) and stirred for 4.5 h at room temperature.The residue after removal of solvent was purified on silica gel columnto provide Example 8AA. ¹³ C. NMR (CDCl₃): (75.48 MHz) 34.075, 37.672,48.941, 48.985, 58.071, 60.640, 65.861, 73.212, 177.975, 118.669,126.535, 126.858, 128.603, 128.815, 129.225, 133.605, 134.172, 137.637,138.273, 155.497.

Example 8R

A solution of the bromoacetate intermediate from Example 8G (0.10 g,0.14 mmol) in methanol was treated dropwise with sodium hydroxidesolution (1N, 1 mL) and stirred at room temperature for 1 hour. Thesolution was diluted with water, acidified with 1N HCl(aq) and extractedinto methylene chloride. The extract was washed with water, brine anddried over magnesium sulfate. The solution was filtered and concentratedto give 90 mg of Example 8R as white solid. MS:(CI,NH3) 671.2 (72%,(M+H)⁺); 669.2 (67%).

                  TABLE 1d                                                        ______________________________________                                         ##STR49##                                                                                                stereo          MS                                Ex. No.                                                                             R.sup.22 = R.sup.23                                                                     X      Y    2:3:4:5                                                                             K.sub.i                                                                            IC.sub.90                                                                          (M + H)                           ______________________________________                                        7A    allyl     OH     OAc  RSSR  +    +++  449.1                             7B    allyl                                                                                    ##STR50##                                                                              RSSR  -    ++   465.2                               7C    allyl                                                                                    ##STR51##                                                                              RSSR  +++  +++  453.2                               7D    R.sup.22 = n-butyl R.sup.23 = allyl                                                      ##STR52##                                                                              RSSR  +++  ++   469.2                               7E    R.sup.22 = n-butyl R.sup.23 = allyl                                                      ##STR53##                                                                              RSSR  ++   +++  449.2                               7F    cyclopropyl methyl                                                                       ##STR54##                                                                              RSSR  +++  +++  481.2                               7G    cyclopropyl methyl                                                                       ##STR55##                                                                              RSSR  ++   +++  461                                 7H    cyclopropyl methyl                                                                       ##STR56##                                                                              RSSR  +    ++   447.2                               7I    cyclopropyl methyl                                                                       ##STR57##                                                                              RSSR  ++   +++  477.2                               7J    2-naphthyl                                                                              OAc    OAc  RSSR  ++   +    691.3                                   methyl                                                                  7K    2-naphthyl                                                                              OH     OAc  RSSR  ++   +    649.3                                   methyl                                                                  7L    2-naphthyl methyl                                                                        ##STR58##                                                                              RSSR  ++   +    633.2                               7M    2-naphthyl methyl                                                                        ##STR59##                                                                              RSSR  +++  +++  653.2                               7N    2-naphthyl methyl                                                                        ##STR60##                                                                              RSSR  +    +    649.2                               7o    2-naphthyl                                                                              OMs    OH   RSSR  ++   +++  685                                     methyl                                                                  7P    2-naphthyl methyl                                                                        ##STR61##                                                                              RSSR  +++  +++  661                                 7Q    2-naphthyl methyl                                                                        ##STR62##                                                                              RSSR  ++   ++   619                                 7R    2-naphthyl methyl                                                                        ##STR63##                                                                              RSSR  +    +    647.3                               7S    2-naphthyl methyl                                                                        ##STR64##                                                                              RSSR  +    ++/+ 691                                 7T    2-naphthyl                                                                              OH     H    RSSR  +++  +    591                                     methyl                                                                  7U    cyclopropyl                                                                             OH     H    RSSR  +++  +++  419                                     methyl                                                                  ______________________________________                                    

                  TABLE 1d                                                        ______________________________________                                                                                    Mass                                                                          Spec                              Ex.                             stereo                                                                              HPLC  M +                               No.  R.sup.22 R.sup.23                                                                       X        Y       2:3:4:5:                                                                            K.sub.i                                                                             H                                 ______________________________________                                        7AA  cyclopropyl                                                                             OMEM     O═  RS-R  +     521                                    methyl                                                                   7AB  cyclopropyl                                                                             hydroxy  HO--N═                                                                            RS-R  +     448                                    methyl                                                                   7AC  cyclopropyl                                                                             hydroxy  MeO--N═                                                                           RS-R  ++    462                                    methyl                                                                   7AD  cyclopropyl                                                                             oxazole  oxazole R--R  ++    442                                    methyl                                                                   7AE  cyclopropyl                                                                             meth-    hydroxy RSSR  ++    449                                    methyl    oxy                                                            7AF  cyclopropyl                                                                             meth-    methoxy RSSR  +     463                                    methyl    oxy                                                            7AG  cyclopropyl                                                                             benzy-   benzyloxy                                                                             RSSR  +     615                                    methyl    loxy                                                           7AH  cyclopropyl                                                                             benzy-   hydroxy RSSR  +     525                                    methyl    loxy                                                           7AI  cyclopropyl                                                                             allyloxy allyloxy                                                                              RSSR        --                                     methyl                                                                   7AJ  cyclopropyl                                                                             allyloxy hydroxy RSSR  ++    475                                    methyl                                                                   7AK  2-naphthyl                                                                              OCH.sub.2 OH                                                                           H       RR-R  +++   621                                    methyl                                                                   7AL  3-        OH       H       RSSR  +++   +++                                    hydroxymeth                                                                   ylbenzyl                                                                 7AM  3-        OH       H       RSSR  ++    +++                                    carbometh-                                                                    oxy benzyl                                                               7AN  benzyl    OH       H       RSSR  +++   +++                               ______________________________________                                    

                                      TABLE 1e                                    __________________________________________________________________________     ##STR65##                                                                                                Mass                                              Ex.                         Spec                                              No. R         X  Y   Ki  IC.sub.90                                                                        (M + H)                                                                            Notes                                        __________________________________________________________________________    7V  cyclopropylmethyl                                                                       F  OH  ++  +++                                                                              437.26                                            7W  allyl     F  OH  ++  ++ 409.23                                            7X  2-naphthylmethyl                                                                        F  OH  ++  +  609.29                                            7Y  2-naphthylmethyl                                                                        N.sub.3                                                                          OH  ++  +  632                                               7Z  cyclopropylmethyl                                                                       OH OH  ++  +++                                                                              435.2                                             8A  cyclopropylmethyl                                                                       OH OMEM       523.4                                             8B  cyclopropylmethyl                                                                       F  OH  ++  +++                                                                              437.3                                             8C  cyclopropylmethyl                                                                       F  OMEM                                                                              +   ++ 525.4                                             8D  2-naphthylmethyl                                                                        F  OMEM                                                                              ++     697.5                                             8E  3-benzyloxy                                                                             F  OH  ++     721                                                   benzyl                                                                    8F  3-hydroxybenzyl                                                                         F  OH  ++  +++                                                                              541.0                                                                  (HPLC)                                                   8G  2-naphthylmethyl                                                                        H  OH  ++  ++/+                                                                             591.5                                                                  (HPLC)                                                   8H  cyclopropylmethyl                                                                       H  OH  +++ +++                                                                              419.1                                                                  (HPLC)                                                   8I  3-hydroxybenzyl                                                                         H  OH  +++ +++                                                                              523.2                                                                  (HPLC)                                                   8J  4-chloromethy                                                                           H  OH  ++     587.2                                                 benzyl           (HPLC)                                                       3-hydroxybenzyl/                                                                        H  OH  ++     569.2                                             8K  4-chloromethy    (HPLC)                                                       benzyl                                                                    8L  3-hydroxybenzyl/                                                                        H  OH  ++     569.2                                                 4-chloromethyl   (HPLC)                                                       benzyl                                                                    8M  4-hydroxymethyl                                                                         H  OH  +++    551                                                   benzyl           (HPLC)                                                   8N  cyclopropylmethyl                                                                       F  H   +   +++                                                                              421.2                                                                  (HPLC)                                                   8O  3-cyanobenzyl                                                                           H  OH  ++  +++                                                                              541.3                                             8P                                                                                 ##STR66##                                                                              H  OH  +++ +++                                                                              575.3                                             8Q  benzyl/H  OH OH  ++  ++ 417.0                                                                              1                                            8R  2-naphthylmethyl                                                                        Br OH  ++  ++/+                                                                             671.2                                                                              2                                            8S  3-hydroxybenzyl/                                                                        H  OH  +++ +++                                                                              417.1                                                                              4                                                H                                                                         8T  N-methylamino                                                                           Br OH  ++  +++                                                                              629.2                                                                              2                                                benzyl                                                                    8U  3-cyanobenzyl                                                                           H  OH  ++  +++                                                                              577.2                                                                              2, 3                                         8V  3-hydroxymethyl                                                                         Br OH  ++  +++                                                                              631.2                                                                              2                                                benzyl                                                                    8W  N-methylamino                                                                           H  OH  +++ +++                                                                              549.3                                                                              2                                                benzyl                                                                    8X                                                                                 ##STR67##                                                                              H  OH  ++  ++ 763.4                                                                              2                                            8Y  3-carbomethoxy                                                                          H  OH  +++ ++ 607.3                                                                              2                                                benzyl                                                                    8Z  3-hydroxymethyl                                                                         H  OH  +++ +++                                                                              551.4                                                                              4                                                benzyl                                                                    8AA allyl     OH OH  ++                                                       8AB 3-carbomethoxy                                                                          H  H   +   +++                                                                              623.3                                                 benzyl                                                                    8AC 4-hydroxymethyl                                                                         H  H   ++  +++                                                                              535.2                                                 benzyl                                                                    8AD benzyl    H  OH  ++  +++                                                                              491.2                                             8AE 3-(H.sub.2 NC(O))                                                                       H  OH  +++ +++                                                                              577.2                                                 benzyl                                                                    8AF 3-(H.sub.2 NC(NOH))                                                                     H  OH  +++ +++                                                                              607.3                                                 benzyl                  (ESI)                                             8AG 3-(H.sub.2 NC(NOH))                                                                     H  OH  +++ +++                                                                              643.3                                                                              3                                                benzyl                  (ESI)                                             8AH 3-(H.sub.2 NC(O))                                                                       H  OH  +++ +++                                                                              613.2                                                                              3                                                benzyl                                                                    8AI 3(H.sub.2 NC(O))-4-                                                                     H  OH  +++ +++                                                                              613.5                                                 fluorobenzyl                                                              8AJ 3-(H.sub.2 NC(NOH))-4-                                                                  H  OH  +++ +++                                                                              643.2                                                 fluorobenzyl            (ESI)                                             8AK 3-(H.sub.2 NC(O))                                                                       H  OH  +++ +++                                                                              649.2                                                                              5                                                benzyl                                                                    8AL 3-(H.sub.2 NC(NOH))                                                                     H  OH  +++ +++                                                                              679  5                                                benzyl                                                                    8AM 3-(3-pyrazolyl)-                                                                        H  OH         623.3                                                 benzyl                                                                    8AN 3-cyanobenzyl                                                                           H  OH  +   +  541.2                                                                              6                                            8AO 3-(H.sub.2 NC(NOH))                                                                     H  OH  ++  +  607.0                                                                              6                                                benzyl                                                                    8AP 3-(H.sub.2 NC(O))                                                                       H  OH  +   +  577.3                                                                              6                                                benzyl                                                                    8AQ 3-carbomethoxy                                                                          H  OH  +   +  607.4                                                                              6                                                benzyl                                                                    8AR 3-hydroxymethyl                                                                         H  OH  ++  +  551.4                                                                              6                                                benzyl                                                                    Notes                                                                         __________________________________________________________________________

1. As in Scheme 9: CF₃ COOH opening of aziridine followed by hydrolysisof the diester.

2. As in Scheme 10.

3. The unsubstituted benzyls in the title structure are replaced withp-fluorobenzyls.

4. As in Scheme 9A: Hydrolysis of monoacetate followed by catalytichydrogenolysis of aziridine ring.

5. The unsubstituted benzyls in the title structure are replaced with3,4-difluorobenzyls.

6. SSS isomer

Using the above-described techniques or variations thereon appreciatedby those of skill in the art of chemical synthesis, the compounds ofTables 3-13 (shown below) can also be prepared.

Prodrugs

For compounds of the present invention having reduceded water solubilityit may be advantageous to prepare prodrugs to enhance the solubility andbioavailability of these compounds. For example, the addition ofionizable groups by derivatization of free hydroxy groups of compoundsof formula (I) with bioreversible esters resulted in greatly improvedwater solubility. Solubility studies were performed by mixing an excessof solid compound in water or aqueous medium for at least 4 hours.Solubility was assessed either visually, if a weighed amount clearlydissolved in a measured volume of solvent (method A), or by HPLC assayof filtrates of saturated solutions (method B). Solubility results aresummarized in Table A below.

                  TABLE A                                                         ______________________________________                                        Ex. No.  Solvent      Method  Solubility (mg/ml)                              ______________________________________                                        5U       water        B       0.01                                            29A      water        B       2.25                                            29B      water        A       >100                                            29C      0.1M citric acid                                                                           A       >20                                             29D      water        A       >200                                            ______________________________________                                    

For such prodrugs of the present invention to be useful therapeuticagents (assuming that the intact esters have relatively little inherentpharmacologic activity), the ester must be hydrolyzed after dosing toyield the parent hydroxy compound. Compounds 29A-29E are hydrolyzed toparent compound 5U in biological fluids in vitro. This was shown asfollows. Plasma was collected from rats, dogs, or human volunteers, andwas used within 24 hours. Prodrug was added to plasma, which had beenwarmed to 37° C., at concentrations of 2-10 μg/ml. After various timesof incubation at 37° C., the hydrolysis reaction was quenched with theaddition of an organic solvent. The organic solvent was used forextraction of 5U, and concentrations of 5U in the plasma aliquots weredetermined using HPLC after extraction. Concentrations of 5U were thusmeasured vs. time of incubation of the prodrug in plasma at 37° C.Similar studies were performed using a homogenate of rat intestinaltissue (10% w/v) as the hydrolysis medium. Results for in vitrohydrolysis of prodrug 29B in dog plasma and rat intestinal homogenate(10% w/v) are given in Table B. Results for in vitro hydrolysis ofprodrug 29C in rat, dog and human plasma are given in Table C. Prodrugs29B, 29C, and 29E were shown to readily convert to parent 5U whenexposed to plasma or intestinal enzymes in vitro. These results indicatethat these prodrugs will convert to 5U in vivo. Other salt forms ofthese compounds, such as prodrugs 29A and 29D, will be similar to theirfree acid or free base forms.

                  TABLE B                                                         ______________________________________                                        Time    % Converted to 5U                                                                          % Converted to 5U                                        (min)   (Dog plasma) (Rat intestine homogenate)                               ______________________________________                                        0       3.4          16.0                                                     5       4.9          16.6                                                     15      5.5          22.7                                                     60      9.3          46.0                                                     120     19.9         47.1                                                     ______________________________________                                    

                  TABLE C                                                         ______________________________________                                        Time  % converted to 5U                                                                          % converted to 5U                                                                          % converted to 5U                             (min) (rat plasma) (dog plasma) (human plasma)                                ______________________________________                                        0     29.4         1.8          6.7                                           5     69.0         3.1          12.9                                          10    74.6         3.3                                                        15                              12.9                                          20    77.6         5.0                                                        30    81.6         6.7          14.5                                          60    90.6         10.1         31.3                                          120   100          15.7         45.8                                          240   100          31.0         73.4                                          360                             74.9                                          ______________________________________                                    

Improved water solubility can result in increasing the extent of oralbioavailability. Oral bioavailability studies were performed in fastedbeagle dogs. Compounds were dosed orally using a solution vehicle or thesolid drug powder filled into hard gelatin capsules. Periodic bloodsamples were taken from each dog and plasma was separated. Plasma drugconcentrations were determined using extraction and HPLC analysis.Generally, after the administration of 5U or its prodrugs 29A-E, theplasma concentrations of 5U were determined, rather than unchangedprodrug concentrations. Oral bioavailability was estimated by comparingthe dose-normalized area under the plasma 5U concentration vs. timecurve (AUC) after oral dosing with the AUC. after intravenousadministration of 5U. Oral bioavailability is expressed as thepercentage of the oral dose absorbed.

Compound 5U has reduced water soluble, and when administered as thesolid powder gave low oral bioavailability. Therefore, in order toattain improved oral bioavailability, 5U was administered using asolution with polyethylene glycol 400 or propylene glycol as thevehicle. However, as the dose of 5U was increased, oral bioavailabilitywas reduced, due to precipitation of 5U from the glycol vehicle uponmixing with the aqueous contents of the gastrointestinal tract. Improvedoral bioavailability was attained when the water soluble prodrugs wereadministered in the solid form, with no added excipients or solvents.One advantage of these water soluble prodrugs is that they can beformulated in conventional solid oral dosage forms, whereas 5U gave loworal bioavailability when dosed in solid form. The advantage of thewater soluble prodrugs is especially clear at high doses. Both prodrugs29B and 29D yielded good oral bioavailability at relatively high doses,whereas the administration of a similar dose of 5U in a non-aqueousvehicle resulted in relatively poor oral bioavailability.

Prodrug 29E resulted in lower bioavailability then prodrugs 29B-D.Additional assays of the plasma samples for intact ester (total of monoand bis ester) was performed by treating plasma with NaOH to hydrolyzeany intact esters. Samples were then extracted again and assayed for 5Uconcentration. The AUC. of intact esters was approximately 2 foldgreater than that of 5U. Thus, plasma levels of both intact prodrug andhydrolysis product can be attained using these water soluble prodrugs.The results of the comparison of the oral bioavailability in dogs of 5Uand its water soluble prodrugs are shown in Table D.

                  TABLE D                                                         ______________________________________                                                                      % Oral Bio-                                     Ex.               Dose        availability of                                 No.     Excipients                                                                              (mg/kg, 5U eq.)                                                                           5U (Mean ± SE)                               ______________________________________                                        5U      glycol    10-15        50 ± 20                                     5U      glycol    40           5 ± 2                                       29B     none      8           29 ± 2                                       28B     none      27          27 ± 6                                       29D     none      31           40 ± 12                                     29E     none       8          12 ± 2                                       ______________________________________                                    

Utility

The compounds of this invention possess retroviral protease inhibitoryactivity, in particular, HIV inhibitory efficacy, as evidenced by theiractivity in the assays, as described below. The compounds of formula (I)possess HIV protease inhibitory activity and are therefore useful asantiviral agents for the treatment of HIV infection and associateddiseases. The compounds of formula (I) possess HIV protease inhibitoryactivity and are effective as inhibitors of HIV growth.

The protease inhibitory activity of the compounds of the presentinvention is demonstrated using standard assays of protease activity,for example, using the assay described below for assaying inhibitors ofHIV protease activity. The ability of the compounds of the presentinvention to inhibit viral growth or infectivity is demonstrated instandard assay of viral growth or infectivity, for example, using theassays described below. The compounds of the present invention inhibitHIV-protease activity in vivo as demonstrated using the animal modelsfor HIV protease inhibition described below. The compounds of thepresent invention demonstrate in vivo HIV inhibitory activity, as shownin the animal models described below. The HIV inhibitory activity in theanimal models described below indicates that the presently claimscompounds are useful for the treatment of HIV infection in humans.

As discussed above, the compounds provided by this invention are alsouseful as standards and reagents for use in tests or assays fordetermining the ability of a potential pharmaceutical to inhibit HIVprotease and/or HIV growth, such as the assays described herein below.Thus, the compounds of the present invention may be provided incommercial kits or containers comprising a compound of this invention,for use pharmaceutical research.

Since the compounds of the present invention inhibit HIV growth andinfectivity, they may be used as HIV antivirals for the inhibition ofHIV in a biological sample which contains HIV or is suspected to containHIV or to be exposed to HIV.

As used herein "μg" denotes microgram, "mg" denotes milligram, "g"denotes gram, "μL" denotes microliter, "mL" denotes milliliter, "L"denotes liter, "nM" denotes nanomolar, "μM" denotes micromolar, "mM"denotes millimolar, "M" denotes molar and "nm" denotes nanometer."Sigma" stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

A compound is considered to be active if it has an IC₅₀ or K_(i) valueof less than about 1 mM for the inhibition of HIV protease or HIV viralgrowth or infectivity.

HIV Protease Inhibition Assay--Spectroscotic Method

Materials:

Protease: Inclusion bodies of E. coli harboring plasmid containing HIVprotease under the control of an inducible T7 promoter were preparedaccording to Cheng et. al (1990) Gene 87: 243. Inclusion bodies weresolubilized in 8M urea, 50 mM tris pH 8.0. Protease activity wasrecovered by dilution 20-fold into buffer containing 50 mM sodiumacetate pH 5.5, 1 mM EDTA, 10% glycerol and 5% ethylene glycol. Enzymewas used at a final concentration of 1.0-10 ug/ml.

Substrate: Peptide of sequence:Ala-Thr-His-Gln-Val-Tyr-Phe(NO₂)-Val-Arg-Lys-Ala, containingp-nitrophenylalanine (Phe(NO₂)), was prepared by solid phase peptidesynthesis as previously described by Cheng et al. (1990) Proc. Natl.Acad. Sci. USA 87: 9660. Stock solutions of 10 mM were prepared in DMSO.

Inhibitory compounds were dissolved in sufficient DMSO to make 2.5 or 25mM stock solutions. All further dilutions were done in DMSO.

Reactions:

Compound (1-5 uL) and HIV protease were mixed in buffer containing 50 mMMES, pH 6.5, 1M NaCl, 1 mM EDTA, 1 mM dithiothreitol, 10% glycerol.Reactions were initiated by the addition of peptide substrate to a finalconcentration of 240 uM, and absorbance at 300 nM monitored for 10 min.Values of Ki for inhibitor binding were determined from percent activitymeasurements in the presence and absence of known concentration ofinhibitor, using a value of 0.07 mM for the Km of the substrate (Chenget al. (1990) Proc. Natl. Acad. Sci. USA 87: 9660).

The HIV-1 protease inhibitory activity of representative compounds ofthe invention is shown in Table 1 and 2.

HIV Protease Inhibition Assay--HPLC Method

Materials:

Protease: Inclusion bodies of E. coli harboring plasmid containingplasmid T1718R with a synthetic gene coding for a single-chain tethereddimer of HIV protease were prepared as described in Cheng et al. (Proc.Natl. Acad. Sci. USA, 87, 9660-9664, 1990). Active protease was preparedas described therein by extraction with 67% acetic acid, dilution33-fold with water, dialysis against water and then against a "refoldingbuffer" consisting of 20 mM MES, 1 mM dithiothreitol and 10% glycerol.Protease was stored as a stock preparation at 10 uM in refolding buffer.

Substrate: Peptide of sequence:aminobenzoyl-Ala-Thr-His-Gln-Val-Tyr-Phe(NO₂)-Val-Arg-Lys-Ala containingp-nitrophenylalanine, was prepared by solid phase synthesis aspreviously described Cheng et al., op.cit. Stock solutions of 2 mMsubstrate were prepared in DMSO.

Inhibitory compounds were dissolved in sufficient DMSO to make 3 mMstock solutions. All further dilutions were prepared in "assay buffer":1M NaCl, 50 mM MES, pH 5.5, 1 mM EDTA, 1 mM DTT, 20% glycerol.

Reactions:

Enzyme reaction: In a 2 ml screw-cap centrifuge tube were added 50 ulprotease (final concentration 0.25 nM) and 0.1 ml inhibitory compound(final concentration 0.1-12,500). After 15 min preincubation at roomtemperature, the reaction was started with the addition of 0.05 mlsubstrate (final concentration 5 uM). Incubation was carried out at 30°C. for 1 hr. The reaction was stopped with 1 ml 0.1M ammonium hydroxide.

HPLC measurement of product formation: The product(aminobenzoyl-Ala-Thr-His-Gln-Val-Tyr) was separated from substrate on aPharmacia MonoQ anion exchange column. The injection volume was 0.2 ml.The mobile phases were: A (20 mM trisHCl, pH 9.0, 0.02% sodium Azide,10% acetonitrile), B (20 mM tris HCl, pH 9.0, 0.02% sodium azide, 0.5Mammonium formate, 10% acetonitrile). The mobile phases were pumped at 1ml/min, with a gradient from 0 to 30% B in 5 min, 100 % B for 4 min towash the column, and a re-equilibration for 4 min. The retention time ofthe product was 3.6 min. Detection with a Shimadzu model RF535fluorescence monitor was at 330 nm (excitation) and 430 (emission). TheKi was calculated from the formula Ki=I/(((Km+S-FA*S)/(FA*Km))-1) whereI=inhibitory concentration, S=substrate concentration, FA=fractionalactivity=cm peak height with inhibitor/cm peak height without inhibitor,and Km=Michaelis constant=20 uM.

HIV RNA Assay

DNA Plasmids and in vitro RNA transcripts:

Plasmid pDAB 72 containing both gag and pol sequences of BH10 (bp113-1816) cloned into PTZ 19R was prepared according toErickson-Viitanen et al. AIDS Research and Human Retroviruses 1989, 5,577. The plasmid was linearized with Bam HI prior to the generation ofin vitro RNA transcripts using the Riboprobe Gemini system II kit(Promega) with T7 RNA polymerase. Synthesized RNA was purified bytreatment with RNase free DNAse (Promega), phenol-chloroform extraction,and ethanol precipitation. RNA transcripts were dissolved in water, andstored at -70° C. The concentration of RNA was determined from the A₂₆₀.

Probes:

Biotinylated capture probes were purified by HPLC after synthesis on anApplied Biosystems (Foster City, Calif.) DNA synthesizer by addition ofbiotin to the 5' terminal end of the oligonucleotide, using thebiotin-phosphoramidite reagent of Cocuzza, Tet. Lett. 1989, 30, 6287.The gag biotinylated capture probe (5-biotin-CTAGCTCCCTGCTTGCCCATACTA3') was complementary to nucleotides 889-912 of HXB2 and the polbiotinylated capture probe (5'-biotin-CCCTATCATTTTTGGTTTCCAT 3') wascomplementary to nucleotides 2374-2395 of HXB2. Alkaline phosphataseconjugated oligonucleotides used as reporter probes were prepared bySyngene (San Diego, Calif.). The pol reporter probe (5'CTGTCTTACTTTGATAAAACCTC 3') was complementary to nucleotides 2403-2425of HXB2. The gag reporter probe (5' CCCAGTATTTGTCTACAGCCTTCT 3') wascomplementary to nucleotides 950-973 of HXB2. All nucleotide positionsare those of the GenBank Genetic Sequence Data Bank as accessed throughthe Genetics Computer Group Sequence Analysis Software Package (DevereauNucleic Acids Research 1984, 12, 387). The reporter probes were preparedas 0.5 μM stocks in 2× SSC (0.3M NaCl, 0.03M sodium citrate), 0.05M TrispH 8.8, 1 mg/mL BSA. The biotinylated capture probes were prepared as100 μM stocks in water.

Streptavidin coated plates:

Nunc-immunomodule microtiter plate strips were coated by addition of 200μL of streptavidin (30 μg/mL, Scripps, La Jolla, Calif.) in freshlyprepared 10 mM sodium carbonate (pH 9.6). Plates were incubatedovernight at 4° C. Streptavidin solution was aspirated from the wellsand a blocking buffer composed of phosphate buffered saline (PBS), 20mg/mL bovine serum albumin (crystalline, nuclease and protease free,Calbiochem) and 100 mg/mL lactose (Sigma) was added to the plates for 3hrs at room temperature. Blocking buffer was removed from the wells,which were allowed to dry overnight at room temperature and subsequentlystored at 4° C. in zip lock bags with desiccant. For the majority of thecompound evaluation experiments, streptavidin coated plates wereobtained from Du Pont Biotechnology Systems (Boston, Mass.)

Cells and virus stocks:

MT-2, CEM, and H9 cells were maintained in RPMI 1640 supplemented with5% fetal calf serum (FCS), 2 mM L-glutamine and 50 μg/mL gentamycin, allfrom Gibco. Laboratory strains of HIV-1 (RF, MN and IIIB) werepropagated in H9 cells in the same medium. Virus stocks were preparedapproximately 1 month after acute infection of H9 cells by clarificationof the tissue culture medium and storage of aliquots at -70° C.Infectious titers of HIV-1(RF) stocks were 1-3×10⁷ PFU (plaque formingunits)/mL as measured by plaque assay on MT-2 cells (see below). Eachaliquot of virus stock used for infection was thawed only once. In somecases, infected H9 cells were shifted to Dulbecco's modified Eagle'smedium 3-10 days before collection of virus in order to generate virusstocks in medium with low biotin content. Clinical isolates of HIV thathad been passaged once in MT-2 cells were used to infect fresh MT-2cells in RPMI medium. Three days after infection, cells were pelleted,resuspended and culture continued in Dulbecco's modified Eagle's mediumas above. Virus stocks of clinical isolates were prepared 10-15 daysafter infection when cytopathic effects were apparent in the culture.

For evaluation of antiviral efficacy, cells to be infected weresubcultured one day prior to infection. On the day of infection, cellswere resuspended at 5×10⁵ cells/mL in RPMI 1640, 5% FCS for bulkinfections or at 2×10⁶ /mL in either Dulbecco's modified Eagles medium,or RPMI 1640 medium minus biotin (Gibco, custom formulation) with 5% FCSfor infection in microtiter plates. Virus was added and culturecontinued for 3 days at 37° C. In some experiments, virus was removedafter an initial adsorption period.

Preparation of HIV-1 infected cell lysates:

HIV-1 infected cells were pelleted by centrifugation. After removal ofthe supernatant the cells were resuspended at a concentration of 1×10⁷cells/mL in 5M guanidinium isothiocyanate solution (GED: 5M guanidiniumisothiocyanate (Sigma), 0.1M EDTA, 10% dextran sulfate). Alternately,cells grown in biotin free tissue culture medium were mixed with 5M GEDto a final concentration of 3M guanidinium isothiocyanate, 0.06M EDTAand 6% dextran sulfate.

HIV RNA assay:

Cell lysates or purified RNA in 3M or 5M GED were mixed with 5M GED andcapture probe to a final guanidinium isothiocyanate concentration of 3Mand a final biotin oligonucleotide concentration of 30 nM. Hybridizationwas carried out in sealed microfuge tubes or in sealed U bottom 96 welltissue culture plates (Nunc or Costar) for 16-20 hours at 37° C. RNAhybridization reactions were diluted three-fold with deionized water toa final guanidinium isothiocyanate concentration of 1M and aliquots (150μL) were transferred to streptavidin coated microtiter plates wells.Binding of capture probe and capture probe-RNA hybrid to the immobilizedstreptavidin was allowed to proceed for 2 hours at room temperature,after which the plates were washed 6 times with DuPont ELISA plate washbuffer (phosphate buffered saline(PBS), 0.05% Tween 20.) A secondhybridization of reporter probe to the immobilized complex of captureprobe and hybridized target RNA was carried out in the washedstreptavidin coated well by addition of 120 μl of a hybridizationcocktail containing 4× SSC, 0.66% Triton X 100, 6.66% deionizedformamide, 1 mg/mL BSA and 5 nM reporter probe. After hybridization forone hour at 37° C., the plate was again washed 6 times. Immobilizedalkaline phosphatase activity was detected by addition of 100 μL of 0.2mM 4-methylumbelliferyl phosphate (MUBP, JBL Scientific) in buffer δ(2.5M diethanolamine pH 8.9 (JBL Scientific), 10 mM MgCl₂, 5 mM zincacetate dihydrate and 5 mM N-hydroxyethyl-ethylene-diamine-triaceticacid). The plates were incubated at 37° C. Fluorescence at 450 nM wasmeasured using a microplate fluorometer (Dynateck) exciting at 365 nM.

Microplate based compound evaluation in HIV-1 infected MT-2 cells:

Compounds to be evaluated were dissolved in DMSO and diluted in culturemedium to twice the highest concentration to be tested and a maximumDMSO concentration of 2%. Further three-fold serial dilutions of thecompound in culture medium were performed directly in U bottommicrotiter plates (Nunc). After compound dilution, MT-2 cells (50 μL)were added to a final concentration of 5×10⁵ per mL (1×10⁵ per well).Cells were incubated with compounds for 30 minutes at 37° C. in a CO₂incubator. For evaluation of antiviral potency, an appropriate dilutionof HIV-1 (RF) virus stock (50 μL) was added to culture wells containingcells and dilutions of the test compounds. The final volume in each wellwas 200 μL. Eight wells per plate were left uninfected with 50 μL ofmedium added in place of virus, while eight wells were infected in theabsence of any antiviral compound. For evaluation of compound toxicity,parallel plates were cultured without virus infection.

After 3 days of culture at 37° C. in a humidified chamber inside a CO₂incubator, all but 25 μL of medium/well was removed from the HIVinfected plates. Thirty seven μL of 5M GED containing biotinylatedcapture probe was added to the settled cells and remaining medium ineach well to a final concentration of 3M GED and 30 nM capture probe.Hybridization of the capture probe to HIV RNA in the cell lysate wascarried out in the same microplate well used for virus culture bysealing the plate with a plate sealer (Costar), and incubating for 16-20hrs in a 37° C. incubator. Distilled water was then added to each wellto dilute the hybridization reaction three-fold and 150 μL of thisdiluted mixture was transferred to a streptavidin coated microtiterplate. HIV RNA was quantitated as described above. A standard curve,prepared by adding known amounts of pDAB 72 in vitro RNA transcript towells containing lysed uninfected cells, was run on each microtiterplate in order to determine the amount of viral RNA made during theinfection.

In order to standardize the virus inoculum used in the evaluation ofcompounds for antiviral activity, dilutions of virus were selected whichresulted in an IC₉₀ value (concentration of compound required to reducethe HIV RNA level by 90%) for dideoxycytidine (ddC) of 0.2 μg/mL. IC₉₀values of other antiviral compounds, both more and less potent than ddC,were reproducible using several stocks of HIV-1 (RF) when this procedurewas followed. This concentration of virus corresponded to -3×10⁵ PFU(measured by plaque assay on MT-2 cells) per assay well and typicallyproduced approximately 75% of the maximum viral RNA level achievable atany virus inoculum. For the HIV RNA assay, IC₉₀ values were determinedfrom the percent reduction of net signal (signal from infected cellsamples minus signal from uninfected cell samples) in the RNA assayrelative to the net signal from infected, untreated cells on the sameculture plate (average of eight wells). Valid performance of individualinfection and RNA assay tests was judged according to three criteria. Itwas required that the virus infection should result in an RNA assaysignal equal to or greater than the signal generated from 2 ng of pDAB72 in vitro RNA transcript. The IC₉₀ for ddC, determined in each assayrun, should be between 0.1 and 0.3 μg/mL. Finally, the plateau level ofviral RNA produced by an effective protease inhibitor should be lessthan 10% of the level achieved in an uninhibited infection.

For antiviral potency tests, all manipulations in microtiter plates,following the initial addition of 2× concentrated compound solution to asingle row of wells, were performed using a Perkin Elmer/Cetus ProPette.

The HIV inhibitory activity of representative compounds of the presentinvention in the RNA assay described above is shown in TABLE 3. The IC₉₀values in TABLE 3 were determined using the assay conditions describedabove under HIV RNA Assay. The IC₉₀ values are indicated as follows:+++=<10 ug/mL; ++=10 to 100 ug/mL; +=>100 ug/mL. The ++/+ is used in thecases where an IC₉₀ was determined to be >50 ug/mL.

HIV Yield Reduction Cell Assay

Materials: MT-2, a human T-cell line, was cultured in RPMI mediumsupplemented with 5% (v/v) heat inactivated fetal calf serum (FCS),L-glutamine and gentamycin. Human immunodeficiency virus strains, HIV(3B) and HIV(RF) were propagated in H-9 cells in RPMI with 5% FCS.Poly-L-lysine (Sigma) coated cell culture plates were prepared accordingto the method of Harada et al. (1985) Science 229: 563-566. MTT,3-(4,5-dimethyl-thiazol-2yl)-2,5-diphenyltetrazolium bromide, wasobtained from Sigma.

Method: Test compounds were dissolved in dimethylsulfoxide to 5 mg/mLand serially diluted into RPMI medium to ten times the desired finalconcentration. MT-2 cells (5×10⁵ /mL) in 2.3 mL were mixed with 0.3 mlof the appropriate test compound solution and allowed to sit for 30minutes at room temperature. HIV (3B) or HIV (RF) (˜5×10⁵ plaque formingunits/mL) in 0.375 ml was added to the cell and compound mixtures andincubated for one hour at 36° C. The mixtures were centrifuged at 1000rpm for 10 minutes and the supernatants containing unattached virus werediscarded. The cell pellets were suspended in fresh RPMI containing theappropriate concentrations of test compound and placed in a 36° C., 4%CO₂ incubator. Virus was allowed to replicate for 3 days. Cultures werecentrifuged for 10 minutes at 1000 rpm and the supernatants containingcell free progeny virus were removed for plaque assay.

The virus titers of the progeny virus produced in the presence orabsence of test compounds were determined by plaque assay. Progeny virussuspensions were serially diluted in RPMI and 1.0 mL of each dilutionwas added to 9 ml of MT-2 cells in RPMI. Cells and virus were incubatedfor 3 hours at 36° C. to allow for efficient attachment of the virus tocells. Each virus and cell mixture was aliquoted equally to two wells ofa six well poly-L-lysine coated culture plate and incubated overnight at36° C., 4% CO₂. Liquid and unattached cells were removed prior to theaddition of 1.5 mL of RPMI with 0.75% (w/v) Seaplaque agarose (FMCCorp.) and 5% FCS. Plates were incubated for 3 days and a secondRPMI/agarose overlay was added. After an additional 3 days at 36° C., 4%CO₂, a final overlay of phosphate-buffered saline with 0.75% Seaplaqueagarose and 1 mg MTT/mL was added. The plates were incubated overnightat 36° C. Clear plaques on a purple background were counted and thenumber of plaque forming units of virus was calculated for each sample.The antiviral activity of test compounds was determined by the percentreduction in the virus titer with respect to virus grown in the absenceof any inhibitors.

HIV Low Multiplicity Assay

Materials: MT-2, a human T-cell line, was cultured in RPMI mediumsupplemented with 5% (v/v) heat inactivated fetal calf serum (FCS),L-glutamine and gentamycin (GIBCQ). Human immunodeficiency virus strainsHIV (3B) and HIV (RF) were propagated in H-9 cells in RPMI with 5% FCS.XTT, benzene-sulfonic acid, 3,3'- 1-(phenyl-amino)carbonyl!-3,4-tetrazolium!bis(4-methoxy-6-nitro)-, sodiumsalt, was obtained from Starks Associates, Inc.

Method: Test compounds were dissolved in dimethyl-sulfoxide to 5 mg/mland serially diluted into RPMI medium to ten times the desired finalconcentration. MT-2 cells (5×10⁴ /0.1 mL) were added to each well of a96 well culture plate and 0.02 mL of the appropriate test compoundsolution was added to the cells such that each compound concentrationwas present in two wells. The cells and compounds were allowed to sitfor 30 minutes at room temperature. HIV(3B) or HIV(RF) (˜5×10⁵ plaqueforming units/mL) was diluted in medium and added to the cell andcompound mixtures to give a multiplicity of infection of 0.01 plaqueforming unit/cell. The mixtures were incubated for 7 days at 36° C.,during which time the virus replicated and caused the death ofunprotected cells. The percentage of cells protected from virus inducedcell death was determined by the degree of metabolism of the tetrazoliumdye, XTT. In living cells, XTT was metabolized to a colored formazanproduct which was quantitated spectrophotometrically at 450 nm. Theamount of colored formazan was proportional to the number of cellsprotected from virus by the test compound. The concentration of compoundprotecting either 50% (IC₅₀) or 90% (IC₉₀) with respect to an uninfectedcell culture was determined.

The HIV inhibitory activity of representative compounds of the presentinvention in the whole cell infectivity assay described above is shownin Table E.

                  TABLE E                                                         ______________________________________                                               Example Number                                                                          IC.sub.90                                                    ______________________________________                                               1C        +++                                                                 1X        +++                                                                 1Z        +++                                                                 1AC       +++                                                                 1AF       +++                                                                 1AH       +++                                                                 1AQ       +++                                                          ______________________________________                                    

The IC₉₀ values in Table 2 are indicated as: +++=<10 ug/mL.

In the Tables herein the Ki values were determined using the assayconditions described above under HIV Protease Inhibtion Assay. The Kivalues are indicated as follows: +++=<10 nM; ++=10 nM to 1 μM; +=>1 μM.

In the Tables herein the IC₉₀ values were determined using the assayconditions described above under HIV RNA Assay. The IC₉₀ values areindicated as follows: +++=<10 μg/mL; ++=10 to 100 μg/mL; +=>100 μg/mL.The ++/+ is used in the cases where an IC₉₀ was determined to be >50μg/mL.

HIV-1/CEM Mouse Xenotransplant Animal Model

The HIV inhibitory activity of the presently claimed compounds in ananimal was demonstrated in an animal model wherein HIV-1 infected humanCEM lymphcyte cells were xenotransplanted in nude mice and the growth ofHIV in vivo in such xenotransplanted CEM cells was monitored. The invivo assay using this model consisted of testing compound in aprophylactic manner, whereby the daily dose of agent was administered toa group of mice one day prior to HIV challenge. The test and controlanimals were followed with drug for a period of 25 days. Upon theexperiment termination and animal sacrifice, serum p24 antigen levels,and relative percent indirect immunofluorescence assay (IFA) positivecell numbers were determined as the experimental endpoint (as describedbelow).

Cell Line and HIV Culture: CCRF-CEM or CEM, a well characterizedtumorigenic and HIV permissive cell line, was obtained from the AmericanType Culture Collection, Rockville, Md. (AYCC. CCL 119) and maintainedin RPMI 1640 medium with 15% heat inactivated fetal calf serum and 50μg/ml gentamicin as described by Wetherall (In: Schellekens andHorzinek, eds., Animal Models in AIDS, Elsevier, Amsterdam, 1990, pp291-302). The cells were propagated at 37° C. in a humid 5% CO₂atmosphere. Stocks of the HIV-1 isolate HTLV-IIIB were acquired from Dr.Neal T. Wetherall, Vanderbilt University, and were harvested fromcultures of chronically-infected CCRF-CEM (CEM) cells obtained from theAmerican Type Culture Collection. For routine propagation, viruscontaining culture fluids were clarified of cells by low speedcentrifugation and passed through 0.45 μm filters. Infectious virionswere quantitated on MT-2 cells in microculture using cytopathic effect(CPE) as the end point for infection.(Scudiero et al., Cancer Res. 1988,48, 4827-4833). The 50% tissue culture infectious dose (TCID₅₀) wascalculated by the method of Reed and Muench (Amer J. Hygiene, 1938, 27,493-497). CCRF-CEM cells used for virus xenotransplantation were acutelyinfected with a stock dilution of HIV-1 at a MOI (input multiplicity ofinfection) of 0.01 followed by adsorption for 1 h at 37° C.

Animals and Cell/HIV Transplantation: Sprague Dawley 21±2 day old femalenude (nu/nu) mice were exposed to 450 Rad's of ¹³⁷ Cs irradiation.Twenty-four hours later, the drug dosing was started. CEM cell cultures,both HIV infected or uninfected, were harvested and washed with serumfree media and reharvested. Cells of a specified number were suspendedin 0.2 ml media and injected subcutaneously (s.c.) into theintrascapular region of the mice, 24 h after drug dosing commenced. Themice were observed the following day and at least three times a week forthe duration of the experiment. At each of these time points the animalgroup weight is determined, and the inoculation site is gently palpatedto determine the date of gross tumor onset. At the termination of anexperiment, the animals were anesthesized and euthanized byexsanguination.

p24 Enzyme Immunoassay: The p24 enzyme immunoassay (EIA) used was theunmodified procedure commercially available from Coulter Corporation(Hialeah, Fla.), which uses a murine monoclonal antibody to the HIV coreprotein coated onto microwell strips. The assay detects p24 gag antigenin culture supernatants, plasma, and serum. Non-specific cross reactionswith mouse serum are not seen with this assay.

Indirect Immunofluorescence Assay (IFA): HIV-1 antigen-expressing cellsare detected by IFA using the method described by Montefiori andMitchell (Virology 1986, 155, 726-731). Slides were prepared by airdrying and fixing in a 50:50 mixture of acetone/methanol for 30 minutes,followed by adding a 1:200 dilution in PBS-BSA (phosphate bufferedsaline containing 0.1% globin-free bovine serum albumin) of high-titerserum from pooled HIV-1 positive individuals (positive by Westernimmunoblot for all HIV-1 antigens).

Anti-HIV IgG then will be detected using a 1:200 dilution offluorescein-conjugated, IgG fraction of goat anti-human IgG (heavy andlight chains specific, Cappel) containing Evan's blue counter stain.Slides were mounted using 50% glycerol and cells examined forfluorescence using a Zeiss KF-2 Epi-fluorescence microscope.

Preparation and Administration of Compounds: Compounds were mixed with0.25% (wt/v) methylcellulose solution, warmed to 37° C., andhomogenized. One drop of Tween 80 was added to the stock suspension (1drop/10-20 ml) and mixed by vortexing. Dilutions of the stock suspensionwere made in methylcellulose/Tween 80 and stored at 4° C. for no morethan one week. The suspensions were gently warmed and vortexed afterremoval from the refrigerator and prior to injection to ensure propersuspension. The compounds were administered BID, i.p. at doses of 30,100, and 300 mg/kg or 60, 200, and 600 mg/kg/day.

The HIV inhibitory activity in vivo in the HIV/CEM mouse xenotransplantanimal model for a representative compound of the invention is shown inTable F below. Data in the p24 EIA and IFA is expressed as a percent ofthe control untreated levels.

                  TABLE F                                                         ______________________________________                                        Compound    Dose         p24 EIA  IFA                                         ______________________________________                                        Ex. 5I      300 mg/kg bid                                                                              37.8     51.5                                                    ip                                                                Ex. 5I      100 mg/kg bid                                                                              76.4     111.3                                                   ip                                                                Ex. 5I      30 mg/kg bid 61.5     116.7                                                   ip                                                                ______________________________________                                    

HIV-1 Protease Transgenic Mouse Model

The in vivo HIV protease inhibitory activity of the presently claimedcompounds was also demonstrated using a transgenic animal model systemwherein the HIV-1 protease protein was expressed in the mouse lens usinga transgene where the HIV-1 protease coding sequence was placed underthe transcriptional control of the mouse alpha A-crystallin promoter.Such transgenic animals were found to display a HIV protease-mediatedcataract phenotype. The HIV protease inhibitory activity of thepresently claimed compounds was measured in this animal system as adelay or prevention of the onset of cataract appearance in the testanimals.

Plasmid Construction: The mammalian expression vector pMSG (Pharmacia)was modified by replacing the MMTV LTR promoter with the 412-bp BglII-BamHI mouse alpha A-crystallin promoter fragment (Chepelinsky et al.Proc. Natl. Acad. Sci. USA, 1985, 82, 2334-2338). The SV40 early spliceand polyadenylation signals were retained and this plasmid was renamedpCSV 19. A single chain, tethered dimeric form of the active HIV-1protease gene (BAA; Cheng et al., Proc. Natl. Acad. Sci. USA, 1990, 87,9660-9664 and Cheng et al., Gene, 1990, 87, 243-248) was modified formammalian cell expression by replacing nucleotides 7 to 90 withCGTAATAGAAGGAGATATAACCATGGAG. The gene was cut with EcoRI and Hind IIIand after blunt-end repair cloned into the Sma I site of the PCSV 19,thus producing pCSV 19-BAA. The mutant form of the construct (BA*A*) wasproduced by site directed mutagenesis (GAT to GGT) resulting in thechange of aspartic acid (25th residue) to glycine in both monomersresulting in an inactive form of the protease.

Construction of Transgenic Mice: 2.5 kb Hind III fragments from the pCSV19-BAA and pCSV 19-BA*A* plasmids were isolated (modified from Sambrookat al., Molecular Cloning, A Laboratory Manual, 2nd Ed., 1989, ColdSpring Harbor Laboratory) and used for the construction of transgenicmice using the pronuclei injection method (Hogan et al., Manipulatingthe Mouse Embryo, A Laboratory Manual, 1986, Cold Spring HarborLaboratory). Mice were screened for the HIV-1 protease transgene byeither Southern blot or Polymerase Chain Reaction (PCR) methods. Mice ofthe FVB/N strain (Taketo et al., Proc. Natl. Acad. Sci. USA, 1991, 88,2065-2069) were used for the construction and breeding of thesetransgenic mice, and were originally obtained from Dr. Carl Hansen (NIH)and bred in our facility. Subsequently, the mice were purchased fromCharles River Laboratory (Portage, Mich.).

Identification of Transgenic Mice: Southern blot analysis (Sambrook etal. vide supra) was performed on DNA purified from tail biopsies (Hoganet al. vide supra) using the 2.5 kb Hind III fragment from pCSV 19-BAAas the probe (³² P labeled). DNA for PCR was prepared from tail biopsiesby overnight digestion with 0.5 mg of Proteinase K (Boehringer-ManheimGmbH) in 100 μl of water and 0.025% SDS. PCR primers specific for themouse c-fos gene and and the transgene's SV40 segment were used as aninternal control in some samples. Each PCR reaction contained 1-2 μl oftail digest, 60 μg of each primer, 200 μM of Perkin Elmer Cetus dATP,dCTP, dGTP,TTP (buffered at pH 8.8) and up to 5 units of Perkin ElmerCetus Ampli/Taq polymerase. The reactions were run on a Perkin Elmer DNAThermal Cycler as follows: 1 min at 94° C., 3 min at 67° C. (2 secextension/cycle) for 35 cycles. The PCR products were analyzed by gelelectrophoresis (1% agarose,0.5 μg/ml of ethidium bromide), and tailsamples with a 625 PCR fragment (SV40 specific) were considered positivefor the transgene. Mice bearing the active HIV-1 protease transgene werealso identified by their cataract phenotype. Progeny of homozygousparent(s) were 100% positive for the transgene and did not requireSouthern/PCR analysis.

Dosing Regimen: Compounds to be tested were pulverized by manualgrinding with mortar and pestle. Just prior to dosing of mice, thecompound was suspended in 0.25% methylcellulose/Tween 80 solution,homogenized in a manual Dounce homogenizer and sonicated for 10 min in asonicating water bath. The volume of suspension was adjusted so that theamount of compound required for dosing one mouse was 0.1-0.2 mL. Inorder to maintain the required mg/kg dose, an average mouse weight foreach group was determined twice a week and the amount of compoundadjusted accordingly. Intraperitoneal (ip) and oral (po) dosing wasperformed using 25 G 5/8 in. injection and 20 G 11/2 in. feedingneedles, respectively. The dosing was performed twice a day (bid) andthe doses were administered 6-8 h apart. Eyes of control and dosedanimals were examined daily by up to 3 individuals, and the day whencataracts became visible to the naked eye was recorded as theexperimental end point (days after birth). Because cataracts do notalways develop in both eyes of individual mice on the same day, each eyewas scored as an independent observation. Results from individual eyeswere used to calculate the average (mean) day of cataract developmentand its standard deviation for each group.

Eye Histology: Eyes were dissected from euthanized mice and fixed with10% neutral buffered formalin. Eye histology was performed at theExperimental Pathology Laboratories (EPL), Inc., Sterling, Va.

Characterization of HIV-1 Protease Transgenic Mice:

Gross appearance: Three lines of mice with the active (BAA) and threelines with the mutant (BA*A*) form of HIV-1 protease gene wereestablished. The eyes of mice with the mutant gene appear identical tothose of normal mice (FIG. 1A), but bilateral cataracts develop in theeyes of mice with the active gene. This phenotype is easily detectedeven by an untrained observer because the inside of cataract eye isopaque and white/gray in color (FIG. 1B). Cataracts appear similar inall transgenic lines.

Time of cataract development: The time when cataract develops variesamong the three transgenic lines bearing the active HIV-1 protease gene(BAA, Appendix 2). Mice of the Tg 61 line develop the phenotypeprenatally (day 18 in utero). Mice of the remaining two lines (Tg 62,and 72) develop the cataracts postnatally (at 24-30 days). Among themice of each individual line, the time difference in cataractdevelopment is less than one week. None of the mice bearing the mutantform of the gene (BA*A*) have developed cataract. Based on this geneticevidence that cataracts develop only in transgenic mice with the activebut not inactive form of HIV-1 protease we conclude this phenotype iscaused by the protease's enzymatic activity.

Method:

A single homozygous male mouse (Tg 72-110) was mated with threenon-transgenic FVB/N females. From each litter, 4-5 mice were used ascontrols, i.e., were dosed with vehicle only (ip or po route). Theremaining mice of each litter (5-7) were dosed (ip or po) with testcompound. When mice were 15 days old, dosing began in two groups of 5mice each with ip injections of 100 mg/kg/BID. The compound wasadministered ip to the mice in the first group until all had bilateralcataracts. For the second group, the compound was administered ip for 5days only and from day 20 via the po route until cataracts appeared. Athird group (7 mice) was dosed ip starting on day 15 but with 400mg/kg/bid. On day 41, when no cataracts had yet developed in this lastgroup, three were removed from treatment, and the remaining four weredosed until day 52. All mice were observed daily for cataract formation.

The results for representative compounds of the present invention in theabove HIV-1 transgenic mouse model are shown in Table G below. Theresults show that the representative compounds of the present inventioneffectively inhibit HIV protease activity in vivo.

                  TABLE G                                                         ______________________________________                                                                             Delay in                                                            Cataract  Cataract                                                            Density   (relative to                             Ex. No.                                                                             Dose/Route   Mouse   (% of control)                                                                          control)                                 ______________________________________                                        1AQ   60 mg/kg ip  Tq 61   46.6                                                     preg days 11-18                                                         1AQ   85 mg/kg ip  Tq 61   20.6                                                     preg days 11-18;                                                              17-18                                                                   1X    15 mg/kg ip  Tq 61   28.8                                                     preg days 11-18                                                         1X    5 mg/kg ip   Tq 61   39.8                                                     preg days 11-18                                                         5I    80 mg/kg bid Tq 72             6 days                                         ip days 15-19/                                                                po days 20 & ff                                                         5I    50 mg/kg bid Tq 72             3.6 days                                       ip days 15-20/                                                                po days 21 & ff                                                         5U    100 mg/kg bid ip                                                                           Tg 72             5 days                                   5U    400 mg/kg bid ip                                                                           Tq 72                                                            days 15-42                                                              ______________________________________                                    

Dosage and Formulation

The antiviral compounds of this invention can be administered astreatment for retroviral infections by any means that produces contactof the active agent with the agent's site of action, the retroviralprotease, in the body of a mammal. They can be administered by anyconventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, butgenerally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice.

The compounds of the present invention can be administered in oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. The compounds ofthe present invention may also be administered in intravenous (bolus orinfusion), intraperitoneal, subcutaneous, or intramuscular form, allusing dosage forms well known to those of ordinary skill in thepharmaceutical arts. An effective but non-toxic amount of the compounddesired can be employed for the inhibition of HIV and the treatment ofHIV infection.

The dosage administered will, of course, vary depending upon knownfactors, such as the pharmacodynamic characteristics of the particularagent and its mode and route of administration; the age, health andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; and the effectdesired.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses may rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three, or four times daily.

The compounds for the present invention may also be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wallknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittant throughout the dosageregimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients, orcarriers (collectively referred to herein as carrier materials) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups and the like, and consistentwith conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamallar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (compositions suitable for administration contain fromabout 1 milligram to about 100 milligrams of active ingredient perdosage unit. In these pharmaceutical compositions the active ingredientwill ordinarily be present in an amount of about 0.5-95% by weight basedon the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch,cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Reminaton'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules arewashed and dried.

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit was 100 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 275 milligrams of microcrystalline cellulose, 11 milligrams ofstarch and 98.8 milligrams of lactose. Appropriate coatings may beapplied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is made isotonic withsodium chloride and sterilized.

Suspension:

An aqueous suspension is prepared for oral administration so that each 5mL contain 100 mg of finely divided active ingredient, 200 mg of sodiumcarboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitolsolution, U.S.P., and 0.025 mL of vanillin.

The compounds of formula (I) of the present invention may beadministered in combination with a second therapeutic agent, such as asecond HIV inhibitory agent or other therapeutic agent for treatment ofHIV associated disease conditions. The compound of formula (I) and suchsecond therapeutic agent can be administered separately or as a physicalcombination in a single dosage unit, in any dosage form and by variousroutes of administration, as described above. The compound of formula(I) may be formulated together with the second therapeutic agent in asingle dosage unit (that is, combined together in one capsule, tablet,powder, or liquid, etc.). When the compound of formula (I) and thesecond therapeutic agent are not formulated together in a single dosageunit, the compound of formula (I) and the second therapeutic agent maybe administered essentially at the same time, or in any order; forexample the compound of formula (I) may be administered first, followedby administration of the second agent. When not administered at the sametime, preferably the administration of the compound of formula (I) andthe second therapeutic agent occurs less than about one hour apart, morepreferably less than about 5 to 30 minutes apart.

The present invention also includes pharmaceutical kits useful, forexample, for the treatment of HIV infection, which comprise one or morecontainers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of formula I. Such kitsmay further include, if desired, one or more of various conventionalpharmaceutical kit components, such as, for example, containers with oneor more pharmaceutically acceptable carriers, additional containers,etc., as will be readily apparent to those skilled in the art. Printedinstructions, either as inserts or as labels, indicating quantities ofthe components to be administered, guidelines for administration, and/orguidelines for mixing the components, may also be included in the kit.

In the present disclosure it should be understood that the specifiedmaterials and conditions are important in practicing the invention butthat unspecified materials and conditions are not excluded so long asthey do not prevent the benefits of the invention from being realized.

The Tables below provide representative compounds of formula (I) of thepresent invention. Specifically incorporated herein by reference is thedisclosure of PCT International Application Publication Number WO93/07128, including Examples Number 1-5763, which are listed in Tables3-12 of such reference.

Tables 2A through 2C and 2d through 2q below set forth representativecompounds of the present invention. ##STR68##

                                      TABLE 2A                                    __________________________________________________________________________    Example                                                                       Number                                                                             R.sup.22  R.sup.23  MS (M + H)                                                                          Ki IC.sub.90                                                                        m.p. (°C.)                        __________________________________________________________________________    2A   CH.sub.2 CHC(CH.sub.3).sub.2                                                            CH.sub.2 CHC(CH.sub.3).sub.2                                                            463   +++                                                                              +++                                                                              165.1                                    2B   CH.sub.2 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                              CH.sub.2 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5                                              563   ++ +++                                                                              120.7                                    2C   CH.sub.2 CHCH.sub.2                                                                     CH.sub.2 CHC(CH.sub.3).sub.2                                                            435   +++                                                                              +++                                                                              62                                       2D   CH.sub.2 CHC(CH.sub.3).sub.2                                                            CH.sub.3  409   ++    sin 65                                                                        108                                      2E   CH.sub.2 C.sub.6 H.sub.4 -p-F                                                           CH.sub.2 C.sub.6 H.sub.4 -p-F                                                           543   +++                                                                              +++                                         2F                                                                                  ##STR69##                                                                              CH.sub.2 C.sub.6 H.sub.5                                                                471   +++                                                                              +++                                         2G   CH.sub.2 CHCH.sub.2                                                                     CH.sub.2 C.sub.6 H.sub.5                                                                457   +++                                                                              +++                                                                              226.5                                    2H   CH.sub.2 C.sub.6 H.sub.5                                                                CH.sub.3  431   ++ +++                                                                              81                                       2I   CH.sub.2 CHC(CH.sub.3).sub.2                                                             ##STR70##                                                                              440   +++                                                                              +++                                                                              76                                       2J   CH.sub.2 C.sub.6 H.sub.4 -m-OCF.sub.3                                                   CH.sub.2 C.sub.6 H.sub.4 -m-OCF.sub.3                                                   675   ++ +++                                                                              128.3                                    2K   CH.sub.2 C.sub.6 H.sub.3 -m-CF.sub.3 -p-F                                               CH.sub.2 C.sub.6 H.sub.3 -m-CF.sub.3 -p-F                                               679   ++ +++                                                                              167.2                                    2L   CH.sub.2 C.sub.6 H.sub.4 -p-OCF.sub.3                                                   CH.sub.2 C.sub.6 H.sub.4 -p-OCF.sub.3                                                   675   ++ +++                                                                              136.8                                    2M   CH.sub.2 C.sub.6 H.sub.3 m-F-m-CF.sub.3                                                 CH.sub.2 C.sub.6 H.sub.3 -m-F-m-CF.sub.3                                                679   ++    162.3                                    __________________________________________________________________________

                                      TABLE 2B                                    __________________________________________________________________________     ##STR71##                                                                    Example                                                                       Number                                                                             R.sup.22   R.sup.23   MS (M + H)                                                                          Ki IC.sub.90                                                                        Notes                                  __________________________________________________________________________    2N   C.sub.6 H.sub.5 CHCHCH.sub.2                                                             C.sub.6 H.sub.5 CHCHCH.sub.2                                                             559.30                                                                              +++                                                                              +++                                                                              1                                      2R   m-F-C.sub.6 H.sub.4 CH.sub.2                                                             m-F-C.sub.6 H.sub.4 CH.sub.2                                                             543.25                                                                              +++                                                                              +++                                                                              1                                      3E   o-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                     o-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                     579.23                                                                              ++ +++                                                                              1                                      3K   m-NH.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                      m-NH.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                      537.28                                                                              +++   3, 4                                   __________________________________________________________________________     NOTES:                                                                        1. Prepared according to the general alkylation procedure (Procedure 5).      Yields of monoalkyl compounds were favored by using one equivalent of         alkylating agent.                                                             2. Prepared by alkylating the appropriate monoalkyl compound.                 3. Isolated as the dihydrochloride salt.                                      4. Preparation: a solution of 41.3 mg of Ex.3B was dissolved in a mixture     of 10 ml of ethanol and 1 ml of 1 N hydrochloric acid. Catalyst (20 mg of     10% palladium on carbon) was added, and the mixture was hydrogenated at       atm pressure for 16 hours. A quantitative yield of Ex. 3K as isolated as      the hydrochloride salt.                                                  

                                      TABLE 2C                                    __________________________________________________________________________     ##STR72##                                                                    Example                                                                            Stereo-                                       Mass Spec                  Number                                                                             isomer                                                                             R.sup.22       R.sup.23      Ki IC.sub.90                                                                         MP (°C.)                                                                    M + 1                                                                               Notes                __________________________________________________________________________    3L   RSSR CH.sub.2 CCH   CH.sub.2 CCH  ++ ++  196-197                                                                            507                        3M   RSSR 2-picolinyl    2-picolinyl   ++ ++  151-153                                                                            509                        3N   RSSR CH.sub.2 CH.sub.2 OCH.sub.3                                                                  CH.sub.2 CH.sub.2 OCH.sub.3                                                                 ++ +   183˜185                                                                      443                        3O   RSSR CH.sub.2 C.sub.6 H.sub.12                                                                    CH.sub.2 C.sub.6 H.sub.12                                                                   ++ +   --   519                        3P   RSSR CH.sub.2 CH.sub.2 C(CH.sub.3).sub.3                                                          CH.sub.2 CH.sub.2 C(CH.sub.3).sub.3                                                         ++ +   242˜245                                                                      495                        3Q   RSSR CH.sub.2 C.sub.6 H.sub.9                                                                     CH.sub.2 C.sub.6 H.sub.9                             3R   RSSR CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3                                                         CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3                                                        +  +   148˜150                                                                      471                        3S   RSSR 3-methyl-5-oxazolinyl-methyl                                                                 H             ++ +   --   464                        3T   RSSR 1-naphthylmethyl                                                                             1-naphthylmethyl                                                                            ++ +   231˜233                                                                      607(85%)                   3U   RSSR 2-naphthylmethyl                                                                             2-naphthylmethyl                                                                            +++                                                                              +++ 202˜204                                                                      607                        3V   RSSR n-butyl        benzyl        +++                                                                              +++ 89˜91                                                                        473                        3W   RSSR CH.sub.2 CHCH.sub.2                                                                          cyclopropylmethyl                                                                           +++                                                                              +++ 173˜175                                                                      421                        3X   RSSR n-butyl        cyclopropylmethyl                                                                           +++                                                                              +++ --   437                        3Y   RSSR CH.sub.2 CHC(CH.sub.3).sub.2                                                                 benzyl        +++                                                                              +++ 173˜174                                                                      485                        3Z   RSSR 3-methyloxoy-olinylmethyl                                                                    3-methyloxoy-olinylmethyl                                                                   +      --   527                        4A   RSSR benzyl         ethyl         +++                                                                              +++ 190˜193                                                                      445                        4B   RSSR benzyl         4-picolinyl   +++                                                                              +++ --   508                        4C   RSSR cyclopropylmethyl                                                                            4-picolinyl   +++                                                                              +++ --   472                        4D   RSSR CH.sub.2 CH.sub.2 OCHCH.sub.2                                                                CH.sub.2 CH.sub.2 OCHCH.sub.2                                                               ++     --   467                        4E   RSSR benzyl         cyclopentylmethyl                                                                           +++                                                                              +++ 198˜200                                                                      499                        4F   RSSR cyclopropylmethyl                                                                            cyclopentylmethyl                                                                           +++                                                                              +++ --   463                        4G   RSSR benzyl         n-propyl      +++                                                                              +++ --   459                        4H   RSSR benzyl-(D.sub.7)                                                                             benzyl-(D.sub.7)                                                                            +++                                                                              +++ --   521                        4I   RSSR cyclopropylmethyl                                                                            cinnamyl      +++                                                                              +++ --   497                        4J   RSSR 2,3,4,5,6-penta-fluoro-benzyl                                                                2,3,4,5,6-penta-fluoro-benzyl                                                               +  +++ 193˜195                                                                      687                        4K   RSSR cyclopropylmethyl                                                                            2-naphthylmethyl                                                                            +++                                                                              +++ 175-178                                                                            521                        4L   RSSR cyclopentylmethyl                                                                            2-naphthylmethyl                                                                            +++                                                                              +++ 89˜92                                                                        549                        4M   RSSR benzyl         2-naphthylmethyl                                                                            +++                                                                              ++  90˜92                                                                        557                        4N   RSSR cyclopropylmethyl                                                                            2-picolinyl   +++                                                                              +++ 220˜222                                                                      472                        4O   RSSR benzyl         2-quinolinylmethyl                                                                          ++ +++ --   558                        4P   RSSR 3-cyanobenzyl  3-cyanobenzyl +++                                                                              +++ 225˜227                                                                      557                        4Q   RSSR 3-benzyloxybenzyl                                                                            3-benzyloxybenzyl                                                                           ++ +++ 140-141                                                                            691                        4R   RSSR 4-phenylbenzyl 4-phenylbenzyl                                                                              ++     109-110                                                                            659                        4S   RSSR 3-allyl        2-naphthylmethyl                                                                            +++                                                                              +++ 72-74                                                                              507                        4T   RSSR n-propyl       2-naphthylmethyl                                                                            +++                                                                              +++ 150˜152                                                                      509                        4U   RSSR n-butyl        2-naphthylmethyl                                                                            +++                                                                              +++ 78-80                                                                              523                        4V   RSSR H              2-naphthylmethyl                                                                            +++                                                                              +++ 210-213                                                                            467                        4W   RSSR 2-adamantylethyl                                                                             2-adamantylethyl                                                                            ++     292˜294                                                                      651                        4X   RSSR H              cyclopropylmethyl                                                                           ++     189-190                                                                            381                        4Y   RSSR 2-picolinyl    2-naphthylmethyl                                                                            ++ +++ 165-166                                                                            558                        4Z   RSSR 4-picolinyl    2-naphthylmethyl                                                                            +++                                                                              +++ 118-121                                                                            558                        5A   RSSR 3-allyl        H             +      180-182                                                                            367                        5B   RSSR 3-allyl        cyclopentylmethyl                                                                           +++                                                                              +++ 190-191                                                                            449                        5C   RSSR 3-allyl        2-picolinyl   ++ +++ 160-162                                                                            458                        5D   RSSR 3-allyl        2-quinolinylmethyl                                                                          +++                                                                              +++ 145-146                                                                            507                        5E   RSSR 3-allyl        4-picolinyl   ++ +++      458                        5F   RSSR 3-benzyloxybenzyl                                                                            3-benzyloxybenzyl                                                                           ++     165-166                         5G   RSSR 3-picolinyl    cyclopropylmethyl                                                                           +++                                                                              +++ 193˜195                                                                      472                        5H   RSSR 3-picolinyl    2-naphthylmethyl                                                                            +++                                                                              +++ 94-96                                                                              558                        5I   RSSR 3-hydroxybenzyl                                                                              3-hydroxybenzyl                                                                             +++                                                                              +++ 101-103                                                                            539                        5J   RSSR vinylbenzyl    vinylbenzyl   +++                                                                              +++ 158-160                                                                            559                        5K   RSSR 3-cyclopropyl-methoxy-benzyl                                                                 3-cyclopropyl-methoxy-benzyl                                                                +      170-172                                                                            697                        5L   RSSR 3-allyloxybenzyl                                                                             3-allyloxybenzyl                                                                            +++                                                                              +   170-172                                                                            619                        5M   RSSR 3-allyloxybenzyl                                                                             3-hydroxybenzyl                                                                             +++                                                                              +++ 78-79                                                                              579                        5N   RSSR 3-ethoxybenzyl 3-ethoxybenzyl                                                                              ++ +   185-186                                                                            595                        5O   RSSR 3-picolinyl    3-picolinyl   +++                                                                              +++ --   509                        5P   RSSR 4-benzyoxybenzyl                                                                             4-benzyoxybenzyl                                                                            +  +   80-81                                                                              719                        5Q   RSSR 2-naphthyimethyl-                                                                            4-fluorobenzyl                                                                              +++                                                                              +++ 105-107                                                                            575                        5R   RSSR 4-hydroxybenzyl                                                                              4-hydroxybenzyl                                                                             +++                                                                              +++ 115-117                                                                            539 (20%)                  5S   RSSR 3-hydroxymethy-benzyl                                                                        3-hydroxymethyl-benzyl                                                                      +++                                                                              +++ 94-95                                                                              567 (40%)                  5T   RSSR 3-carbomethoxy-benzyl                                                                        3-carbomethoxy-benzyl                                                                       +++                                                                              +++ --   623 (40%)                  5U   RSSR 4-hydroxy-methylbenzyl                                                                       4-hydroxy-methylbenzyl                                                                      +++                                                                              +++ 190-195                                                                            567                        5V   RSSR 3-formylbenzyl 3-formylbenzyl                                                                              +++                                                                              +++ 175-176                                                                            563 (30%)                  5W   RSSR 4-cyanobenzyl  4-cyanobenzyl +++                                                                              +++ 140-143                                                                            557 (15%)                  5X   RSSR 4-formylbenzyl 4-formylbenzyl                                                                              +++                                                                              +++ 90-91                                                                              563 (52%)                  5Y   RSSR 4-hydroxybenzyl                                                                              2-propyl      +++                                                                              +++ 246-248                                                                            475 (80%)                  5Z   RSSR 3-hydroxybenzyl                                                                              2-propyl      +++                                                                              +++ 212-213                                                                            475 (90%)                  6A   RSSR 3-carboxybenzyl                                                                              3-carboxybenzyl                                                                             +++                                                                              +++ 190-195                                                                            189                        6B   RSSR 4-carboxybenzyl                                                                              4-carboxybenzyl                                                                             ++ ++  210-211                                                                            189                        6C   RSSR 3-formaldoxime-benzyl                                                                        3-formaldoxime-benzyl                                                                       +++                                                                              +++ 185-189                                                                            593 (2%)                   6D   RSSR cyclopropylmethyl                                                                            3-hydroxybenzyl                                                                             +++                                                                              +++ 233-234                                                                            486                        6E   RSSR cyclopropylmethyl                                                                            4-hydroxybenzyl                                                                             +++                                                                              +++ 234-236                                                                            486                        6F   RSSR 5-chloro-2-thienyl-methyl                                                                    5-chloro-2-thienyl-methyl                                                                   ++ +++      587                        6G   RSSR cyclobutylmethyl                                                                             cyclobutylmethyl                                                                            +++                                                                              +++      463                        6H   RSSR cyclopentylmethyl                                                                            cyclopentylmethyl                                                                           +++                                                                              +++      491                        6I   RSSR n-butyl        CH.sub.2 CHC(CH.sub.3).sub.2                                                                +++                                                                              +++                                 6J   RSSR n-butyl        cyclopentylmethyl                                                                           +++                                                                              +++      465                        6K   RSSR 2-quinolinyl-methyl                                                                          2-quinolinyl-methyl                                                                         ++ +        609                        6L   RSSR 2-propyl       2-picolinyl   ++ +++      460   1                    6M   RSSR p-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                         p-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                        ++ ++       567.29                                                                              1                    6N   RSSR (CH.sub.3).sub.2 N CH.sub.2 CH.sub.2                                                         (CH.sub.3).sub.2 NCH.sub.2 CH.sub.2                                                         +  +        469.32                                                                              1                    6o   RSSR benzyl         H             +++                                                                              +++      417.22                                                                              1                    6P   RSSR o-F-C.sub.6 H.sub.4 CH.sub.2                                                                 o-F-C.sub.6 H.sub.4 CH.sub.2                                                                ++ +++      543.25                                                                              1                    6Q   RSSR m-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                         m-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                        +++                                                                              +++      567.29                                                                              1                    6R   RSSR (CH.sub.3).sub.2 NCH.sub.2 CH.sub.2                                                          (CH.sub.3).sub.2 NCH.sub.2 CH.sub.2                                                         +  +        468.62                                                                              1                    6S   RSSR m,p-F.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                         m,p-F.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                        +++                                                                              +++      579.23                                                                              1                    6T   RSSR p-CH.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                          p-CH.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                         +++                                                                              +++      535.30                                                                              1                    6U   RSSR p-ClC.sub.6 H.sub.4 CH.sub.2                                                                 p-ClC.sub.6 H.sub.4 CH.sub.2                                                                +++                                                                              +++      575.19                                                                              1                                                                       (.sup.35 Cl)               6V   RSSR p-FC.sub.6 H.sub.4 CH.sub.2                                                                   ##STR73##    +++                                                                              +++ 183.4                                                                              489.26                                                                              1a                   6W   RSSR p-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                          p-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                         ++ +        643.24                                                                              1                    6X   RSSR m-ClC.sub.6 H.sub.4 CH.sub.2                                                                 m-ClC.sub.6 H.sub.4 CH.sub.2                                                                +++                                                                              +++ 210.3                                                                              575.19                                                                              1                                                                       (.sup.35 Cl)               6Y   RSSR m-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                          m-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                         ++ +        643.24                                                                              1                    6Z   RSSR m-NO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                          m-NO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                         +++                                                                              +++ 248.3                                                                              597.23                                                                              1                    6ZA  RSSR m-CH.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                          m-CH.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                         +++                                                                              +++      535.30                                                                              1                    6ZB  RSSR o-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                         o-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                        +  ++       567.29                                                                              1                    6ZC  RSSR m,m-F.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                         m,m-F.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                        ++ +++ 167.9                                                                              579.23                                                                              1                    6ZD  RSSR o-ClC.sub.6 H.sub.4 CH.sub.2                                                                 o-ClC.sub.6 H.sub.4 CH.sub.2                                                                ++ +++      575.56                                                                              1                                                                       (.sup.35 Cl)               6ZE  RSSR m-BrC.sub.6 H.sub.4 CH.sub.2                                                                 m-BrC.sub.6 H.sub.4 CH.sub.2                                                                +++                                                                              +++ 210.7                                                                              665.00                                                                              1                    6ZF  RSSR p-FC.sub.6 H.sub.4 CH.sub.2                                                                  H             +++                                                                              +++ 188.9                                                                              435.21                                                                              1                    6ZG  RSSR p-BrC.sub.6 H.sub.4 CH.sub.2                                                                 p-BrC.sub.6 H.sub.4 CH.sub.2                                                                ++ +++      663.09                                                                              1                                                                       (.sup.79 Br)               6ZH  RSSR m-ClC.sub.6 H.sub.4 CH.sub.2                                                                  ##STR74##    +++                                                                              +++ 126.0                                                                              505.23 (.sup.35                                                                     1l)                  6ZI  RSSR m-NH.sub.2 C.sub.6 H.sub.4 CH.sub.2 (HCl)                                                    m-NH.sub.2 C.sub.6 H.sub.4 CH.sub.2 (HCl)                                                   +++                                                                              +++      537.29                                                                              2                    6ZJ  RSSR m,m-Cl.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                        m,m-Cl.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                       ++ ++  231.1                                                                              642.10                                                                        (.sup.35 Cl)               6ZK  RSSR m-(NH.sub.2 CH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                m-(NH.sub.2 CH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                               ++ ++       565.32                     6ZL  RSSR m-NO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                          H             +++                                                                              +++      462.20                     6ZM  RSSR m-(NHCHO)C.sub.6 H.sub.4 CH.sub.2                                                            m-(NHCHO)C.sub.6 H.sub.4 CH.sub.2                                                           +++                                                                              +++      593.28                                                                              3                    6ZN  RSSR m-(NHCOCH.sub.3)C.sub.6 H.sub.4 CH.sub.2                                                     m-(NHCOCH.sub.3)C.sub.6 H.sub.4 CH.sub.2                                                    +++                                                                              +++      621.31                     6ZQ  RSSR m,p-(HO).sub.2 C.sub.6 H.sub.4 CH.sub.2                                                      m,p-(HO).sub.2 -C.sub.6 H.sub.4 CH.sub.2                                                    +++                                                                              +++      571.24                     6ZP  RSSR                                                                                ##STR75##                                                                                    ##STR76##    +  ++       667.34                     __________________________________________________________________________     All of the compounds of Table 2C were synthesized using procedure 5. In       the  instance that the alkylation can not be performed using conditions       described  previously, due to reactivity of a functional group or groups      that may be part of  the alkylating agent, then functional group              protection may be carried out, based  on the methods for functional group     protection described in .W. Greene and P.G.M.  Wuts, "Protecting Groups i     Organic Synthesis", 2nd edition, Wiley (1991). Upon  successful               alkylation, liberation of the desired functional group would take place       based on the aforementioned reference.                                        1. Prepared according to the general alkylation procedure (Procedure 5).      Yields of monoalkyl compounds were favored by using one equivalent of         alkylating agent.                                                             1a. Prepared by alkylating the appropriate monoalkyl compound.                2. A mixture of Example 6Z (41.3 mg, 0.069 mmole), ethanol (10 mL),           hydrochloric acid (lN, 1 mL), and palladium on carbon (10%, 20 mg) was        stirred at atmospheric pressure under an atmosphere of hydrogen for 16        hours. The catalyst was removed by filtration, and the filtrate was           evaporated to dryness to give the desired product.                            3. The compound from Example 6ZI was converted to the free base by            distribution between ethyl acetate and sodium hydroxide (1N). The ethyl       acetate solution was evaporated to give a residue of the free base. The       free base was refluxed in excess butyl formate for 16 hours, after which      the solution was evaporated to dryness to give a residue of the               bisformamide 6ZM.                                                        

Synthesis of compounds of the invention in Table 2d is described infurther detail below.

Example 9A

To a solution of bis m-(HO--N═CH)--C₆ H₄ CH₂ cyclic urea (0.297, 0.502mmol) in methanol (5 ml) was added borane-pyridine complex (0.464 g,5.02 mmol) at -10° C. and the resultant mixture was stirred for 15minutes. After treated with 4M HCl in dioxane (5 ml), the reactionmixture was allowed to stir to room temperature for additional 1.5hours. The solution was neutralized with sat. NaHCO₃ to pH=8, washedwith water and dried over MgSo₄. After removal of solvents, the residuewas purified on silica gel plate with ethylacetate:dichloromethane:methanol (50:50:2) to give 60 mg of a solid,M.P. 214°-216° C. ¹ H NMR (CD₃ OD): δ 8.03(s, 1H), 7.46-7.06 (m, 18H),4.74 (d, J=13.9 Hz, 1H), 4.73 (d J=13.9 Hz, 1H), 3.92(s,2H), 3.62-3.59(bs, 4H), 3.07-2.91(m,6H) ¹³ C NMR (CD₃ OD): 163.88, 149.70, 141.26,141.23, 139.92, 139.39, 138.73, 134.91, 131.50, 131.41, 130.64, 130.00129.72, 129.64, 129.57, 129.53, 128.47, 127.45 127.42, 127.31, 71.96,71.92, 67.42, 67.11, 58.65, 57.09, 57.03, 33.62, 33.57, MS: 594 (100%)595 (M+H,60%).

Example 9C

To a stirred solution of bis m-(HO--N═CH)--C₆ H₄ CH₂ cyclic urea (257mg, 0.434 mmol), sodium cyano-borohydride (290 mg, 4.6 mmol) and traceamount of methyl orange in methanol (10 ml) at room temperature wasadded dropwise 2N HCl at a rate sufficient to maintain a pH of 3-4 over3 hours. The methanol was removed by rotary evaporation. The residue waspurified on a reverse phase TLC plate with 90% methanol in water to givethe product. ¹ H NMR (CD₃ OD): δ 7.33-7.09 (m, 18H), 4.75 (d, J=13.9 Hz,2H), 3.93 (s,4H), 3.61-3.56 (m, 4H), 3.06-2.94 (m, 6H); ¹³ C NMR (CD₃OD): 162.42, 139.72, 137.88, 137.79, 129.92, 129.20, 128.31, 128.14,128.06, 126.02, 70.36, 65.49, 57.40, 55.59, 32.09.

Example 9E

A solution of Example 9C (30 mg) in methanol was treated with 4M HCl indioxane at room temperature. All solvents were removed under vacuum togive hydroxylamine hydrochloride. ¹ H NMR (CD₃ OD): δ 7.44-7.23 (m,14H),6.99 (d, J=6.2 Hz, 4H), 4.65 (d, J=14.3 Hz,2H), 4.35(S, 4H), 3.70-3.66(m, 4H), 3.12-3.05 (m,4H), 2.89-2.85 (m,2H); ¹³ C NMR(CD₃ OD): δ 163.68,141.13, 140.39, 123.09, 132.03, 131.06, 130.59, 130.50, 129.59, 127.48,71.82, 68.23, 57.40, 56.12, 33.70.

Example 9B

An unpurified sample of example 9C was purified on TLC plate usingacetic acid:ethyl acetate:dichloromethane (5:50:45) to give the aceticacid salt. ¹ H NMR (CD₃ OD): δ 7.35-7.08 (m, 18H), 4.74 (d, J=13.9 Hz,2H), 3.97(s, 4H), 3.62-3.53(m, 4H), 3.06-2.88 (m, 6H), 1.97 (s, 6H).

Example 9D

A solution of bis (m-CHO--C₆ H₄ CH₂) cyclic urea (119 mg, 0.212 mml) andO-benzylhydroxylamine hydrochloride (203 mg, 1.27 mmol) inpyridine/ethanol (6 ml 1:1) was refluxed for 3 hours. After removal ofsolvent, the residue was purified on T.L.C. plate with 15% ethyl acetatein dichloromethane to give the product (164 mg) as a solid, M.P.170.5°-171° C. ¹ H NMR(CDCl₃): δ 8.01 (s, 2H), 7.39-7.07 (m, 28H), 5.09(s, 4H), 4.81 (d, J=14.3 Hz, 2H), 3.59 (bs, 2H), 3.52 (d, J=11.0 Hz,2H), 3.07-2.88 (m, 8H); ¹³ C NMR(CDCl₃): 162.14, 148.55, 139.40, 138.62,137.39, 132.50, 130.50, 129.43, 128.87, 128.62, 128.35, 128.27, 128.87,127.57, 126.56, 126.46, 76.34, 71.32, 64.55, 55.57, 32.70; MS 790(M+NH₄,100%).

Example 9F

By the procedure given above Example 9C, a solution of Example 9D (60mg, 0.078 mmol), sodium cyanoborohydride (70 mg, 1.1 mml), trace amountsof methyl orange in methanol was treated with 2N HCl (approx. 0.5 ml).Purification on T.L.C. plate with 40% ethyl acetate in methylenechloride gave the product (30 mg). ¹ H NMR (CDCl₃): δ 8.05 (s,1H),7.43-7.06 (m, 28H), 5.13 (s, 2H), 4.90 (d, J=14.3 Hz, 1H), 4.87(d,J=14.3 Hz, 1H), 4.61(s, 2H), 3.98 (s, 2H), 3.59-3.49 (m, 4H), 3.07-2.95(m, 6H). ¹³ C NMR(CDCl₃): δ 161.98, 148.59, 139.48, 138.86, 138.32,138.05, 137.74, 137.48, 132.56 130.61, 129.87, 129.51, 128.91, 128.67,128.65, 128.44, 128.37, 128.11, 127.91, 127.86, 127.66, 126.59, 126.56,126.40, 77.20, 76.41, 76.15, 71.52, 71.48, 64.33, 64.11, 56.26, 55.58,55.57, 33.79, 32.47. MS: 792 (M+NH₄, 40%) 775 (M+H,100%).

Example 9G

To a suspension solution of bis (m-(HO)--C₆ H₄ CH₂) cyclic urea (280 mg,0.52 mmol) and Cs₂ CO₃ (1.5 g, 4.6 mmol) in THF (4 ml) was addedmethylchloroformate (122.9 mg, 1.3 mm) and the resulting mixture wasstirred at room temperature overnight. The mixture was filtered throughcelite and concentrated to give a residue which was purified on T.L.C.plate with 15% ethyl acetate in methylene chloride to give the product(220 mg) as a solid, M.P. 146°-147° C. ¹ H NMR (CD₃ OD): d 7.34-6.95 (m,18 m), 4.78 (d.J=14.3 Hz, 2H), 3.78 (s. 6H), 3.68 (bs, 2H), 3.61 (d,J=11.4 Hz, 2H), 3.10-2.83 (m, 6H). ¹³ C NMR (CD₃ OD): 162.22, 154.08,151.28 139.74, 129.28, 129.14 128.11, 126.52, 125.99, 121.63, 119.85,70.44, 66.14, 55.46, 54.51, 32.22; MS: 655 (M+H, 100%).

Example 9H

A solution of Example 9P (50 mg, 0.085) in methanol (2 ml) was treatedwith sodium borohydride (32 mg, 0.85 mmol) at room temperatureovernight. After removing the solvent, the mixture is purified on T.L.C.plate with EtOAc/CH₂ Cl₂ (1:1) to give a good yield of the desiredproduct (two stereoisomers): MS=612 (M+NH₄ +, 100%); HRMS: 595.3177 forC₃₇ H₄₃ N₂ O₅ (M+H); ¹ H NMR (CD₃ OD): δ 7.36-7.06 (M, 18H), 4.82(d,J=6.3 Hz, 1H) 4.78 (d,J=6.6 Hz,1H), 4.77 (d,J=13.9 Hz, 2H), 3.64-3.57(m, 4H), 2.10-2.92 (m, 6 Hz), 1.41 (d,J=6.6 Hz, 3H), 1.40 (d,J=6.3 Hz,3H); ¹³ C NMR (CD₃ OD): δ 163.93, 148.07, 141.33, 139.36, 130.69,129.59, 129.55, 127.62, 127.59, 126.01, 125.90, 72.04, 70.60, 70.56,67.30, 67.05, 57.27, 57.12, 33.66, 25.55.

Example 9I

To a solution of Example 9S (100 mg) in tetrahydrofuran (1 ml) was addedmethyl amine (0.4 ml, 40% in water) and the resulting solution wasstirred overnight. After concentration and purification on the plate,the product was obtained in good yield. ¹ H NMR(CD₃ OD) δ 7.40 (m,18H)4.69 (d, J=14.3 Hz,2H) 3.93 (s,4H) 3.66-3.64 (m,4H) 3,35-3.02 (m,4H)2.90-2.81 (m,2H) 2.52 (s,6H); ¹³ CNMR(CD₃ OD) δ 163.75, 141.31, 140.86,139.58, 130.70, 130.64, 129.79, 129.51, 129.33, 128.86, 127.41, 71.91,67.55, 57.22, 56.21, 35.51, 33.63.

Examples 9J and 9K

By the procedure described previously for preparation of Example 9D, andsubstituting b-ethanolamine and trace amounts of molecular sieves(powder) in ethanol. The reaction mixture was filtered through Celiteand concentrated to give a residue, which was purified on reverse phraseT.L.C. plate with 90% methanol in water to the desired compounds.

Example 9J: ¹ H NMR (CD₃ OD): δ 8.31 (s, 2H), 7.67 (d, J=7.7 Hz, 2H),7.59 (s, 2H), 7.43-7.03 (m, 14H), 4.74 (d, J=14 Hz, 2H), 3.81-3.58 (m,12H), 3.10-2.86 (m, 6H); ¹³ C NMR (CD₃ OD): 164.97, 163.73, 141.22,140.14 137.66, 133.06, 130.65, 130.53, 130.06, 129.56, 128.50, 127.46,71.93, 67.90, 64.26, 62.29, 57.20, 33.68, MS: 649 (M+H, 100%).

Example 9K: ¹ H NMR (CD₃ OD): δ 8.31 (s,1H), 7.68-7.03 (m, 18H), 5.33(s, 1H), 4.76 (d, J=13.9 Hz, 1H), 4.75 (d, J=14.3 Hz, 1H), 3.81-3.55 (m,10H), 3.12-2.7 (m, 8H); ¹³ C NMR (CD₃ OD): 164,97, 163.78, 141.29,141.24, 140.18, 139.39, 137.63, 133.06, 130.67, 130.64, 130.53, 130.48,130.05, 129.55, 129.50, 128.86, 128.49, 127.47, 127.45, 127.20, 104.35,71.98, 67.90, 67.40, 64.25 62.39, 57.22, 57.11, 53.23, 33.67; M.S.: 649(M+H, 100%).

Example 9L

To a solution of Example 5I (0.7 g, 1.3 mmol) and triethylamine (0.263g, 2.6 mmol) in THF (5 ml) was added benzyl isocyanate (0.346 g, 2.6mmol) and the resulting solution was stirred at room temperatureovernight. After removal of all the volatiles, the residue was purifiedon T.L.C. plate to give 0.7 g of a solid, M.P. 150° C. (decompose). ¹ HNMR (CD₃ OD): δ 7.33-6.83 (m, 28H), 4.74 (d, J=13.9 Hz, 2H), 4.30 (s,4H), 3.64-3,57 (m,4H), 3.13-2.91 (m, 6H); ¹³ C NMR (CD₃ OD): 162.54,155.68, 151.33, 139.88, 139.30, 138.64, 129.29, 129.20, 128.24, 128.18,127.02, 126.90, 126.13, 125.81, 122.44, 120.55, 70.44, 65.28, 55.20,44.31, 32.28; M.S: 805 (M+H, 100%).

Example 9M

To a solution of Example 5I (100 mg, 0.186 mmol) triethylamine (38 mg.0.39 mmol) in THF (1 ml) was added methyl isocyanate (27 mg. 0.47 mmol)at room temperature and the resulting mixture was stirred overnight.After removal of all volatile reagents, a residue was purified on T.L.C.plate with 40% ethyl acetate in dichloromehane to give 51 mgs of asolid, M.P. 150° C. (decompose). ¹ H NMR (CD₃ OD) δ 7.44-6.99 (m, 18H),4.82 (d, J=14.2 Hz, 2H), 3.69-3.65 (m, 4H), 3.15-2.95 (m,6H), 2.84 (s,6H). ¹³ C NMR (CD₃ OD): 163.96, 157.56, 152.92, 141.31 140.83, 130.66,130.55, 129.58, 127.46, 127.17, 123.70, 121.95, 71.88, 67.02, 56.67,33.65, 27.57. M.S.: 670 (M+NH, 100%).

Example 9N

A solution of bis (m-bromobenzyl) cyclic urea (MEM-protected) (0.84 g, 1mmol), propargyl alcohol (0.224 g, 4 mmol), tetrakis (triphenylphoshine)palladium (0.116 g, 0.1 mmol), copper iodide (0.019 g, 0.1 mmol) intriethylamine (5 ml) was refluxed under nitrogen overnight. Afterevaporation of all volatiles, a residue was diluted with ether (20 ml)and filtered through Celite. The filtrate was concentrated and purifiedon T.L.C. plate to give 400 mg of MEM-protected-mono/coupling product.Deprotection of 170 mg of the coupled product by the standard proceduregave 130 mg of the desired product. ¹ H NMR (CD₃ OD): δ 7.50-7.09 (m,18H), 4.72 (d, J=13.9 Hz, 1H), 4.69 (d, J=13.4 Hz, 1H), 4.46 (s, 2H),3.75-3.68 (m, 4H), 3.18-2.86 (m, 6H). ¹³ C NMR (CD₃ OD): 163.61, 141.99,141.07, 139.73, 133.64, 133.54, 131.91, 131.76, 131.47, 130.57, 130.50,129.81, 129.59, 129.19, 127.51, 124.69, 123.46, 89.28, 85.09, 71.93,71.91, 68.12, 67.75, 57.07, 57.03, 51.15, 33.60, 33.59; M.S.: 639/641(M+H, 100%), 656/658 (M+NH₄, 100%).

Examples 9O and 9P

A solution of bis (m-Br--C₆ H₄ CH₂) cyclic urea (425 mg, 0.64 mmol),1-ethoxy-1-trimethylstannyl ethylene (833 mg, 3.84 mmol) and Pd(PPh₃)₄(37 mg, 0.032 mmol) in THF (5 ml) was refluxed under N₂ overnight. Aftercooling to room temperature, the reaction mixture was diluted with ether(10 ml) and filtered through silica gel to give two products. Furtherpurification on T.L.C. plate with 20% ethyl acetate in methylenechloride gave Example 9Q (107 mg, M.P. 190°-191° C.) and Example 9P (225mg, M.P. 158°-159° C.)

Example 9O: ¹ H NMR (CDCl₃): δ 7.78 (d, J=7.3 Hz, 1H), 7.71 (s, 1H),7.42-7.02 (m, 16H), 4.81 (d, J=13.9 Hz, 1H), 4.77 (d, J=13.9H, 1H), 3.71(bs, 2H), 3.62-3.54 (m, 2H), 3.20-2.85(m, 8H), 2.50 (s, 3H); ¹³ C NMR(CDCl₃): 198.27, 161.86, 140.38, 139.29, 139.22, 138.81, 137.22, 133.99,132.36, 130.65, 130.09, 129.36, 129.32, 128.99, 128.86, 128.66, 127.70,127.55, 126.61, 122.53, 71.38, 65.24, 65.12, 55.83, 55.59, 32.77, 26.58,M.S: 644/646 (M+NH₄, 100%).

Example 9P: ¹ H NMR (CDCl₃): δ 7.78-7.03 (m, 18H), 4.83 (d, J=14.3 Hz,2H), 3.73-3.62 (m,4H), 3.17-3.08 (m, 4H), 2.92-2.89 (m, 2H), 2.49 (s,6H); ¹³ C NMR (CDCl₃): 198.03, 161.83, 139.40, 138.78, 137.12, 133.87,129.29, 129.04, 128.74, 128.52, 127.36, 126.46, 71.25, 71.15, 65.32,55.82, 30.73, 26.51; M.S.: 608 (M+NH₄, 100%).

Example 9Q

A solution of Example 9P (84 mg, 0.142 mmol) and hydroxylaminehydrochloride (59.4 mg, 0.854 mmol) in pyridine/ethanol (6 ml, 1:1) wasrefluxed overnight. Evaporation of all solvents under vacuum gave aresidue which was purified on preparative T.L.C. plates with ethylacetate: methylene chloride: methanol (50:50:2) to give 71 mg of asolid, M.P. 200°-202° C. ¹ H NMR (CD₃ OD): δ 7.67-7.07 (m, 18H), 4.74(d, J=13.9 Hz, 2H), 3.64-3.62 (m, 4H), 3.09-2.89 (m, 6H), 2.17 (s, 6H);¹³ C NMR(CD₃ OD): 163.94, 155.43, 141.23, 139.46, 138.97, 130.77,130.65, 129.69, 129.37, 128.10, 127.47, 126.32, 72.02, 67.16, 57.08,33.62, 11.96; M.S.: 621, (M+H, 100%).

Example 9R

A solution of Example 9Q (50 mg, 0.066 mmol) in methanol (2 ml) wastreated with sodium borohydride (25 mg, 0.66 mmol). After the reactionswas completed, the mixture was washed with hydrochloric acid(2N), waterand dried with magnesium sulfate. Concentration gave a residue which waspurified to give a good yield of the desired product: MS 629.2015 forC₃₁ H₃₈ N₂ OrBr; ¹ H NMR (CD₃ OD); δ 7.42-7.01 (m, 18H), 4.79-4.60 (m,3H), 3.65-3.58 (m, 4H), 3.08-2.78 (m, 6H), 1.40-1.37 (m, 3H); ¹³ CNMR(CD₃ OD): δ 163.73, 148.11, 142.08, 141.19, 139.26, 133.64, 131.75,131.45, 130.61, 129.62, 129.57, 129.19, 129.15, 127.61, 127.49, 127.17,126.05, 123.46, 72.06, 71.92, 70.59, 68.20, 6.27, 57.12, 57.04, 53.68,25.55.

Example 9S

Prepared according to the general alkylation and deprotection procedures(see Procedure 5) MS: 603.2163 (M+H⁺), 100%); HR Mass Spec: 603.2163 forC₃₅ H₃₇ N₂ O₃ Cl₂ (M+H); ¹ HNMR (CD₃ OD) δ 7.39-7.02 (m, 18H), 4.68(d,J=14.3 H₂, 2H), 4.55 (S, 4H), 3.65-3.59 (m,4H), 3.09-3.04 (m, 2H),3.00 (d,J=14.3 H₂, 2H), 2.93-2.84 (m, 2H), ¹³ HNMR (CD₃ OD, ppm):162.26, 139.74, 138.47, 138.16, 129.35, 129.16, 128.82, 128.48, 128.09,127.38, 125.97, 70.47, 66.14, 55.69, 45.19, 32.20.

Example 15XC

A solution of Example 9S (100 mg., 0.166 mmol) in tetrahydrofuran (1 ml)was treated with methyl amine (40% in H₂ O, 1 ml) and the resultingsolution was stirred at room temperature overnight. After the solutionwas concentrated on a rotary evaporator, the residue was obtained andwas purified on Prep. T.L.C. to give a good yield of a neutral productwhich was acidified with 4M HCl in ether to give the desired product.MS: 593 (M+H⁺, 100%); HRMS: 593.2483 for C₃₇ H₄₅ N₄ O₃ ; ¹ H NMR (CD₃OD) δ 7.38-7.07 (m, 18H), 4.69 (d, J=14.3 Hz,2H), 3.93 (S, 4H),3.66-3.64 (m, 4H), 3.09-3.02 (m, 4H), 2.90-2.81 (m, 2H), 2.52 (S, 6H);¹³ CNMR (CD₃ OD, ppm) 163.75, 141.30, 140.85, 139.58, 130.70, 130.64,129.79, 129.51, 129.32, 128.85, 127.41, 71.91, 67.55, 57.22, 56.21,35.50, 33.63.

Example 15XE

To a suspension of NaH (240 mg, 60% in mineral oil, 6 mmol) in DMF (4mL) was added MEM-protected Example 11N (694 mg. 0.98 mmol), and3-chloromethylpyridine (492 mg., 3 mmol); and the resulting mixture wasstirred at room temperature overnight. After the reaction mixture wasfiltered through Buchner funnel, the filtrate was treated with 4M HCl indioxane(15 ml) for 16 hours and then was neutralized with sat. NaHCO₃,to pH=7. After general workup, the resulting crude was purified onT.L.C. plate using ethyl acetate to give the product in a good yield.MS: 538 (M+H⁺, 100%); HRMS 538.2693 for C₃₃ H₃₆ O₄ N₃ ¹³ C NMR (CD₃ OD)ppm 163.67, 151.07, 149.16, 141.11, 139.33, 135.91, 130.59, 130.51,130.48, 129.62, 128.53, 138.24, 127.51, 127.47, 135.28, 71.96. 71.80,68.68, 66.98, 64.81, 56.71, 55.10, 33.73, 33.66.

Example 15XF

To a solution of Example 9S (100 mg, 0.166 mmol) in DMF (2 ml) was addedK₂ CO₃ (138 mg, 1.0 mmol) and diethylamine hydrochloride (80 mg, 1.0mmol) and the resulting mixture was stirred for 24 hrs. The mixture wasdiluted with EtOAc and washed with water. After the organic layer wasdried over MgSO₄, the solution was concentrated under vacuum to give 70mg. of the product. MS: 677 (M+H, 100%); HRMS: 677.4444 for C₄₃ H₅₇ N₄O₃ ; ¹ H NMR(CDCl₃): δ 7.26-6.96 (m, 18H), 4.84 (d,J=14.3 Hz, 2H),3.50-3.46 (m, 4H), 3.35 (s, 4H), 2.97-2.78 (m, 6H), 2.36 (q, J=6.9 Hz,4H), 0.90 (t, J=6.9 Hz, 6H), ¹³ C NMR (CDCl₃,) δ 161.98, 139.52, 138.52,138.17, 129.99, 129.46, 128.46, 128.25, 128.84, 127.84, 126.30, 71.09,64.23, 56.98, 55.54, 46.42, 32.62, 11.31.

Example 15XG

The experimental procedure is similar as preparation of Example 15XF.MS: 667. (MtH, 100%); HRMS: 667.3394 for C₄₁ H₄₃ N₆ O₃ ; ¹³ C NMR (CD₃OD, ppm): 163.76, 141.27, 141.21, 138.82, 130.62, 130.28, 129.70,129.56, 127.88, 127.45, 71.93, 67.37, 57.11, 51.36, 33.75; ¹ H NMR (CD₃OD): δ 7.69, (s, 2H), 7.35-6.92 (m, 22H), 5.19 (s, 4H), 4.62 (d,J=14.3Hz, 2H), 3.52-3.50 (m, 4H), 3.03-2.70 (m, 6H).

Example 15XH

To a solution of MEM-protected Example 4P (366 mg, 0.5 mmol) in THF (15mL) at -78° C. was dropwise added ^(t) Buli (1.7M, 2.59 ml, 4.4 mmol),and the resulting solution was allowed to warm to room temperature. Themixture was diluted with ether washed with saturated NH₄ Cl, water, anddried ever MgSO₄. After concentrated on a rotary evaporator, a residuewas obtained and was purified on T.L.C. plate with 10% EtOAc in CH₂ Cl₂to give a good yield of the product; MS: 675.5 (M+H), 100%); HRMS:675.3805 for C₄₃ H₅₁ N₂ O₅ ; ¹ H NMR (CDCl₃): δ 7.56-7.54 (m, 2H), 7.43(s,2H), 7.33-7.25 (s,10H), 7.08-7.06 (m, 4H), 4.88 (d,J=14.3 Hz, 2H,3.64-3.53 (m,4H), 3.09-2.87 (m, 6H), 1.29 (s, 18H); ¹³ C NMR (CDCl₃): δ209.24, 161.87, 139.35, 139.05, 138.23, 131.66, 129.43, 128.70, 128.36,126.96, 126.62, 71.58, 64.76, 55.80, 44.21, 32.89, 27.94.

Example 15XI

To a solution of trifluoromethyl trimethylsilane (312 mg. 2.2 mmol), inTHF (3 ml) in an ice-water bath was added a solution of MEM-protectedExample 5V (400 mg, 0.55 mmol) in THF (2 mL); and then to the resultingsolution was added tetrabutylammonium fluoride catalyst (TBAF, 3 mg,0.011 mmol. After the reaction mixture was stirred at 0° C. for 40 min.,the cooling bath was removed and the reaction mixture was brought toroom temperature and was continued for an additional hour. The reactionmixture was then treated with 4M HCl in dioxane (5 mL) overnight.General workup and purification on TLC plate with 20% EtOAc in CH₂ Cl₂to furnish a quantitative yield of Example 15XI: MS: 703 (M+H, 100%);HRMS: 703.2611 for C₃₇ H₃₇ N₂ O₅ F₆ ; ¹³ C NMR (CDCl₃, ppm) 162.40,139.70, 138.02, 135.76, 129.61, 129.18, 128.30, 128.14, 126.74, 126.58,126.03, 71.39 (q, J=32.4 Hz), 70.55, 65.88 (d, J=6.2 Hz), 55.66, 32.12;¹⁹ F NMR (CDCl₃) 79.72 (q.J=6.0 H₂); ¹ H NMR (CDCl₃): δ 7.83-7.04 (m,18H), 5.01-4.98 (m, 2H), 4.72 (d,J=14.2 Hz, 2H), 3.67-3.58 (m, 4H),3.09-2.92 (m, 6H).

Example 15XJ

To a solution of N-SEM protected imidazole (552 mg., 2.78 mmol) in THF(10 ml) at -78° C. was added n-Buli (1.6M, 2.5 mL, 4 mmol) dropwise andthe resulting solution was allowed to warm to -20° C. over one hour.After a solution of MEM-protected 5V(510 mg., 0.697 mmol) in THF (10 mL)was added, the reaction mixture was allowed to warm to room temperatureand was stirred for an additional hour. Workup by general procedure andpurification on T.L.C. plate with 50% ether in CH₂ Cl₂ gave an oilyintermediate (160 mg., 21.3% of yield), which was deprotected with 4MHCl in dioxane to give the product in good yield: MS: 695 (M+H, 100%);HRMS: 695.2977 for C₄₁ H₃₉ N₆ O₅, ¹³ C NMR (CD₃ OD, ppm): 183.16,164.07, 146.27, 141.34, 139.59, 137.92, 135.08, 133.06, 130.70, 130.53,120.74, 120.57, 127.45, 71.92, 66.93, 56.72, 33.72; ¹ H NMR (CD₃ OD): δ8.50 (s, 2H), 8.29-8.27 (m, 2H), 7.61-7.21 (m, 18H), 4.94 (d, J=14.3 Hz,2H), 3.77-3.72 (m, 4H), 3.20-3.09 (m, 6H).

Example 15XK

A solution of Example 15XE in MeOH was acidified with 4M HCl in dioxaneto give the product: ¹ H NMR (CD₃ OD): δ 8.58 (d,J=l.l Hz, 2H), 8.42(dd,J,=1.1 Hz, J=4.0 Hz, 1H), 7.78 (bs, 1H), 7.30-7.00 (m, 12H), 6.78(d,J=6.4 Hz, 2H), 4.61 (d,J=14.2 Hz, 1H), 4.32 (dd, J=39.8 Hz, J=14.2Hz, 2H), 4.03-3.99 (m, 1H), 3.71-3.62 (m, 4H), 3.21 (d,J=13.2 Hz, 1H),3.02-2.90 (m, 4H), 2.72-2.66 (m, 1H), ¹³ C NMR (CD₃ OD, ppm) 163.80,148.66, 143.75, 142.32, 141.38, 140.85, 140.44, 137.59, 130.46, 129.60,129.54, 128.43, 128.20, 127.66, 127.53, 71.54, 70.84, 68.41, 67.56,64.67, 56.67, 54.02, 34.36, 33.05.

Example 15XL

The experimental procedures is similar as preparations Example 9N: MS:632 (M+N14, 100%); HRMS: 615.2853 for C₃₉ H₃₉ N₂ O₅ ; ¹ H NMR (CD₃ OD):δ 7.32-6.99 (M, 18H), 4.82 (d,J=1.3 Hz, 2H), 4.65 (d,J=13.9 Hz, 2H),4.37 (s, 2H), 3.31-3.30 (m, 4H); 3.08-3.04 (m, 2H), 3.98 (d,J=13.9 Hz,2H), 2.89-2.84 (m, 2H).

Example 15XM

To a solution of MEM-protected-m-iodobenzyl cyclic urea (980 mg., 1.07mmol) in THF (10 ml) at -78° C. was added t-BuLi (1.7M in hexane, 2.64mL, 4.5 mmol) and the resulting solution was stirred for another 30mins. The N,N-dimethyl trifluoroacetamide (560 mg., 4 mmol) was addedand the mixture was stirred for 2.5 hours. The mixture was diluted withether and acidified with 2N HCl to pH=1. The ether layer was neutralizedand washed with water, brine, and dried over MgSO₄. The solution wasconcentrated to give a residue which was purified on silica gel columnwith gradient solvents (0-20% ethyl acetate in CH₂ Cl₂) to give an oilyintermediate (350 mg).

The oil was dissolved in CH₂ Cl₂ (5 ml) and was treated with 4M HCl indioxane overnight. General workup and purification on Prep. T.L.C. platewith 40% EtOAc in CH₂ Cl₂ gave the the product (300 mg) in 40.2% yield.MS: 699.4 (M+H, 100%); HRMS: 699.2286 for C₃₇ H₃₃ N₂ O₅ F₆ ; ¹ H NMR(CD₃ COCD₃): δ 7.97 (bs, 4H), 7.73-7.59 (m, 4H), 7.14-6.96 (m, 10H),4.75 (d,J=13.9 Hz, 2H), 3.72-3.63 (m, 4H), 3.32 (d,J=14.3 Hz, 2H),3.18-3.13 (m, 2H), 2.95-2.79 (m, 4H); ¹⁹ FNMR (CD₃ COCD₃): δ72.54; ¹³ CNMR (CD₃ COCD₃) 180.83 (q,J=34.3 Hz), 162.39, 141.27, 141.06, 137.90,131.60, 130.43, 130.35, 130.23, 129.73, 129.16, 127.05, 117.62(q,J=291.4 Hz), 71.83, 67.40, 56.55, 33.59.

Example 15XN

To a solution of MEM-protected 4P (750 mg, 1.02 mmol) in THF (20 mL) wasadded ethyl magnesium bromide (2M in Et₂ O, 4 mL) and the resultingmixture was allowed to reflux for 2 hours. After removing all solventson rotary evaporator, the resulting residue was dissolved in MeOH (15mL) and was treated with 4M HCl in dioxane overnight. After generalworkup and purification on T.L.C. plate with 40% EtOAc in CH₂ Cl₂.Example 15XN was obtained (600 mg) in 95.2% yield. MS: 636 (M+N H₄,100%); HRMS: 619.3181 for C₃₉ H₄₃ N₂ O₅ ; ¹ H NMR (CDCl₃): δ 7.77-7.71(m, 4H), 7.39-7.22 (m, 10H), 7.06-7.03 (m, 4H), 4.83 (d,J=14.3 Hz, 2H),3.75 (bs,2H) 3.64-3.60 (m,2H), 3.53 (S, 2H), 3.14 (d,J=14.31 Hz, 2H),3.10 (d,J=11.6 Hz, 2H), 2.95-2.86 (m, 2H), 2.87 (q,J=7.3 Hz, 4H), 1.12(t,J=7.3 Hz, 6H); ¹³ C NMR (CDCl₃, ppm) 200.85. 161.88, 139.36, 138.72,136.92, 133.70, 129.31, 128.75, 128.66, 128.54, 127.09, 126.50, 71.28,65.28, 55.84, 32.70, 31.70, 8.04.

Example 15XP

The experimental procedure of Note 5, Table 2D was followed: MS: 649(M+H⁺, 100%); ¹ H NMR (CD₃ OD): δ 7.62-7.08 (m, 18H), 4.76 (d,J=13.9 Hz,2H), 3.63-3.60 (m, 4H), 3.10-2.91 (m, 4H), 2.97 (d,J=13.9 Hz, 2H), 2.78(q,J=7.7 Hz, 4H), 1.06 (t,J=7.7 Hz, 6H); ¹³ C NMR(CD₃ OD, ppm) 162.46,158.95, 139.71, 138.00, 136.45, 129.31, 129.17, 128.29, 128.11, 126.81,126.02, 125.09, 70.53, 65.63, 55.57, 32.17, 18.67, 9.88.

Example 15XQ

To a solution of MEM-protected-m-iodobenzyl cyclic urea (1 g, 1.07 mmol)in THF (15 mL) at -78° C. was dropwise added t-Buli (1.7M in hexane, 2.5mL) and the resulting solution was stirred for another 30 minutes.Sulfur dioxide gas was introduced into the basic solution at the sametemperature for 15 mins. The mixture was allowed to warm to R.T. over 2hours and then was cooled to -78° C. again. Sulfuryl chloride (0.72 g.,5.35 mmol) was added and the resulting mixture was allowed to warm toR.T. and stirred overnight. After all volatile reagents and solventswere removed under vacuum, the residue was dissolved in THF (10 mL) at-60° C. and was treated with excess ammonia gas for 10 minutes. Thefinal mixture was diluted with EtOAc and washed with water, brine anddried over anhydrous MgSO₄ followed by filtration. The solvents wereremoved on a rotary evaporator and the residue was deprotected bygeneral procedure. Finally, the crude was purified on T.L.C. plate andfurther purified on HPLC to give the desired product in moderated yield.MS: 682 (M+NH₄, 10%); HRMS: 665.2103 for C₃₃ H₃₇ N₄ O₇ S₂ ; ¹³ C NMR(CD₃ CCD₃, ppm) 162.33, 145.25, 141.16, 140.81, 133.59, 130.38, 129.86,129.21, 127.77, 126.95, 125.85, 71.87, 67.52, 56.78, 33.56; ¹ H NMR (CD₃OD): δ 8.19-7.32 (m, 18H), 5.06 (d,=14.3 Hz, 2H), 4.08-3.95 (m, 4H),3.49-3.16 (m, 6H)

Example 15XR

The experimental procedure in Note 5 of Table 2d was followed. MS: 745(M+18, 100%); HRMS: 729.2500 for C₃₇ H₃₅ N₄ O₅ N₆ ; ¹ H NMR (CD₃ OD): δ7.47-7.39 (m, 6H), 7.29-7.24 (m, 8H), 7.06-7.03 (m, 4H), 4.71 (d,J=13.9Hz, 2H), 3.66 (S, 2H), 3.62 (d,J=11.7 Hz, 2H), 3.08 (d,J=12.5 Hz, 2H),2.98 (d,J=14.2 Hz, 2H), 2.95-2.89 (m, 2H), ¹³ C NMR (CD₃ OD, ppm)163.87, 141.26, 139.71, 132.08, 131.04, 130.64, 129.75, 129.56, 128.95,128.92, 127.45, 122.57 (q,J=273.1 Hz), 72.02, 67.42, 57.02, 33.67; ¹⁹ FNMR(CD₃ OD) 67.75.

Example 15XS

The experimental procedure of Note 5, Table 2D was followed. Theobtained product was further purified on chiral-HPLC to give theproduct: MS: 621 (M+H⁺, 100%); ¹ H NMR CDCl₃ +CD₃ OD(1:1)!: δ 7.26-6.76(m, 18H), 4.47 (d,J=14.3 Hz, 2H), 3.24-3.03 (m, 4H), 2.76-2.56 (m, 6H,)1.86 (s, 6H); ¹³ C NMR CDCl₃ +CD₃ OD(1:1), ppm! 163.28, 155.56, 140.48,138.78, 138.18, 130.34, 130.09, 129.22, 129.12, 127.62, 127.04, 125.84,71.45, 66.00, 56.42, 33.15, 12.25;

Example 15YG

To a stirred mixture of cyclic urea Example 5I (Table 2c) (300 mg, 0.56mmol) and anhydrous cesium carbonate (912 mg, 2.8 mmol) in dioxane, freebase of N-(2-chloroethyl) morpholine (2.5 g, 16.8 mmol) was added(prepared by dissolving 3.1 g of the hydrochloride in 5 mL of water and5 mL of sat'd NaHCO₃, extracting with 100 mL of Hexane, drying overMgSO₄, and concentrating) (Thompson; et al. J. Med. Chem. 1992, 35,1698) and heated up to 80° C. for 2 days. The mixture was filtered,rinsed with chloroform and purified on silica gel (1:5Methanol:Chloroform) to give 339 mg (79%) pure product. M. P. 110°-112°C. M. S. 765(M+1, 100%).

Example 15YH

The intermediate was prepared by alkylating the appropriatemonoalkylated compound with m-cyanobenzyl chloride. Lithium aluminumhydride (158 mg, 4.18 mmol) was added to AlCl₃ (180 mg, 1.39 mmol) inether at 0° C. The mixture was warmed up to RT and stirred for 15 min.Then a solution of the above intermediate (950 mg, 1.16 mmol) in etherwas added dropwise. The mixture was stirred at RT for 1 h, quenched with1 mL of H₂ O, 1 mL of 5% NaOH and washed with H₂ O, sat'd NaCl and driedover MgSO₄. Following the same hydrolysis procedure, the product wasisolated (70 mg) in 10% yield. M. P. 132°-134° C. M.S. 566 (M+1, 100%).

Example 15YI

To the mixture of 1 mL of DMF and 4 mL CH₂ Cl₂, oxalyl chloride (0.72mL, 2M in CH₂ Cl₂) was added dropwise at -20° C. under N₂. After 20 min,500 mg (0.65 mmol) of bis(N-m-benzoic acid) cyclic urea Example 6A(Table 2c) and 0.14 mL (2 mmol) of N-methyl-morpholine were added. Themixture was stirred at -20° C. for 20 min. N-methylhydroxylaminehydrochloride (217 mg, 4 mmol) and an additional 0.56 mL (8 mmol) ofN-methylmorpholine were added. The reaction mixture was diluted withethyl acetate, washed with cold 5% HCl, sat'd NaHCO₃, H₂ O, brine andpurified on silica gel (1:95 Methanol:chloroform). Following the samehydrolysis procedure, the product (80 mg) was isolated in 20% yield. M.P. 223°-224° C.

Example 15YJ

Using an analogous procedure to that reported by Paul Unangst, et al.(in J. Med. Chem. 1992, 35, 3691-3698) the title compound can beprepared from the hydroxyamidine. To a stirred solution ofhydroxyamidine analog (150 mg, 0.19 mmol) containing triethylamine (0.13mL, 0.95 mmol), ethyl chloroformate in 10 mL chloroform was addeddropwise at 0° C. The mixture was stirred at RT for 2 h and washed withwater, brine and dried over MgSO₄. The residue was purified on silicagel (1:1 ethyl acetate: methylene chloride). The product (137 mg, 76%yield) was isolated as ester intermediate.

To the above ester intermediate, toluene was added and the solution washeated up to 110° C. for 48 h. The solvent was removed on rotaryevaporator. Following the same hydrolysis procedure. The product(45 mg)was isolated in 35% yield. M. P. 223°-224° C. (decomp.).

Example 15YF

A solution of bis(N-m-benzaldehyde) cyclic urea Example 5V (Table2c)(120 mg, 0.21 mmol) containing small amount of 3A molecular sieveswas treated with toluenesulfonyl-hydrazide dropwise at 0° C. under N₂.The mixture was stirred at RT for overnight. The solvent was removed onrotary evaporator and purified on silica gel (1:4 ethylacetate:methylene chloride) to give 92 mg (52%) pure product. M. P.169°-171° C.

Example 15YK

To a solution of N-SEM-imidazole (396 mg, 2 mmol) in THF (10 mL) at -78°C. was added n-BuLi (5 mmol, 3.1 mL) dropwise and the resultant mixturewas stirred for 30 minutes, and to this was added a solution of zincchloride (410 mg, 3 mmol) in THF (5 mL). After the resulting solutionwas allowed to warm to room temperature, a solution of m-iodobenzylcyclic urea (466 mg, 0.5 mmol) in THF (2 mL) and Pd(PPh₃)₄ (77 mg, 0.07mmol) were added under nitrogen and resultant mixture was allowed toreflux overnight. Work-up and deprotection by general procedure,followed by purification on TLC plate with 50% EtOAc in CH₂ Cl₂ gaveExample 15YK as a solid. ¹ H NMR (CD₃ OD) δ 7.74-7.09 (m, 22 H), 5.34(s, 2H), 4.84 (d, J=13.3 Hz, 1H), 4.68 (d, J=14.3 Hz, 1H), 3.76-3.69 (m,4H), 3.60 (t, J=8.0 Hz, 2H), 3.18-3.03 (m, 4H), 2.96-2.88 (m, 2H), 0.90(t, J=8.0 Hz, 2H), 0 00 (s, 9H); ¹³ C NMR (CD₃ OD): ppm 164.91, 150.71,143.28, 142.52, 142.43, 141.37, 141.11, 139.14, 135.08, 135.06, 134.43,134.33, 133.13, 132.84, 132.72, 132.34, 131.96, 131.38, 131.35, 131.22,131.03, 130.94, 130.91, 130.84, 129.79, 128.84, 128.80, 124.79, 96.36,77.82, 73.27, 73.24, 69.49, 68.97, 68.84, 58.54, 58.32, 35.16, 34.91,19.94, 0.00.

Example 15YL

To a solution of N-SEM protected pyrazole (1.98 g., 10 mmol) in THF (40mL) at -78° C. was added n-BuLi (1.6M, 7.5 mL, 12 mmol) dropwise and theresulting solution was stirred for an additional half hour, and thentriisopropylborate (9.4 g, 50 mmol) was added. After being allowed towarm to room temperature over 2 hours, the reaction mixture wasacidified with 2N HCl, extracted with ether, washed with water andbrine, and dried over MgSO₄. Filtration and concentration gaveN-SEM-3-hydroxyboric-pyrazole (2.4 g, 100%) as a solid. ¹ H NMR (CD₃ OD)δ 7.57 (S, 1H), 6.80 (s, 1H), 5.70 (s, 2H), 3.57 (t, J=7.8 Hz, 2H), 0.89(t, J=8.0 Hz, 2H), 0.00 (s, 9H); ¹³ C NMR (CD₃ OD): ppm 138.54, 115.65,78.98, 65.98, 17.31, -2.30.

To a solution of m-iodobenzyl cyclic urea (932 mg, 1 mmol) in THF (5 mL)was added N-SEM-3-hydroxyboric-pyrazole (968 mg, 4 mmol), Pd(PPh₃)₄(57.8 mg, 5%) and Na₂ CO₃ (1.7 g in H₂ O (4 mL) under nitrogen and theresultant mixture was allowed to reflux over 48 hours. The organic layerwas concentrated on rotary evaporatior to give a residue, which wasdeprotected by the general procedure, followed by purification on TLCplate with 20% EtOH in hexane to give Example 15YL (560 mg, 87.8%) as asolid. MS 639 (M+H⁺, 100%); HRMS calcd for C₃₉ H₃₉ N₆ O₃ 639.3084, Found639.3081; ¹ H NMR (CD₃ OD) δ7.76-7.69 (m, 6H), 7.45-7.15 (m, 14H), 6.66(s, 2H), 4.87 (d, J=14.3 Hz, 2H), 3.77 (b, 4H), 3.19-2.98 (m, 6H); ¹³ CNMR (CD₃ OD) ppm 162.82, 140.19, 139.01, 129.67, 129.22, 128.96, 128.59,127.06, 126.49, 125.03, 102.41, 71.02, 66.69, 56.37, 32.65.

Example 15YM

A solution of Example 15YL (200 mg) in methanol (5 mL) was treated withHCl gas for 2 seconds and the solvent was removed under full vacuum togive Example 15YM as a solid. ¹ H NMR (CD₃ OD) δ 8.34-8.32 (m, 2H),7.76-7.74 (m, 2H), 7.73-7.66 (m, 2H), 7.55-7.50 (m, 4H), 7.15-7.09 (m, 8H), 6.89-6.86 (m, 4H), 4.58 (d, J=13.9 Hz, 2H), 3.88-3.78 (m, 4H), 3.32(d, J=13.9 Hz, 2H), 3.08-3.04 (m, 2H), 2.78-2.69 (m, 2H); ¹³ C NMR (CD₃OD) ppm 161.86, 147.23, 139.72, 139.50, 135.07, 132.00, 129.53, 129.04,128.00, 127.92, 126.03, 125.97, 125.74, 104.78, 70.21, 67.75, 56.28,32.27.

Example 15YN

To a solution of N-SEM protected pyrazole (780 mg., 3.9 mmol) in THF (40mL) at -78° C. was added t-BuLi (1.7M, 2.8 mL, 4.7 mmol) dropwise andthe resulting solution was stirred for an additional 30 minutes. Thesolution was transferred to another solution of MEM-protectedm-cyanobenzyl cyclic urea (732 mg., 1 mmol) in THF (10 mL) at -78° C.and the resulting reaction mixture was allowed to warm to roomtemperature and was stirred overnight. After evaporation of allvolatiles, the residue was diluted with methanol (20 mL) and thentreated with 4M HCl in dioxane (20 mL) overnight. Workup by generalprocedure and purification on reverse phase T.L.C. plate with 70% MeOHin H₂ O gave Example 15YN in good yield: MS: 695 (M+H, 100%); HRMS calcdfor C₄₁ H₃₉ N₆ O₅ 695.2983, Found 695.2967; ¹³ C NMR (CD₃ OD): ppm183.16, 164.07, 146.27, 141.34, 139.59, 137.92, 135.08, 133.06, 130.70,130.53, 120.74, 120.57, 127.45, 71.92, 66.93, 56.72, 33.72; ¹ H NMR (CD₃OD) δ 8.50 (s, 2H), 8.29-8.27 (m, 2H), 7.61-7.21 (m, 18H), 4.94 (d,J=14.3 Hz, 2H), 3.77-3.72 (m, 4H), 3.20-3.09 (m, 6H).

Example 15BI

A solution of MEM-protected compound 12J (0.94 g, 1.0 mmol) was treatedwith n-BuLi (1.6M, 1.6 mL) at -78° C. for 20 minutes, followed byquenching with N-methoxy-N-methyl benzyloxyacetamide (1.35 g, 6 mmol),prepared by a reaction of benzyloxyacetyl chloride withN-methoxy-N-methylamine in pyridine and CH₂ Cl₂ at room temperature.Removal of MEM-groups by general hydrolysis procedure followed bypurification by preparative T.L.C. gave compound 15BI in moderate yield.¹ H NMR (CDCl₃) δ 7.72-7.66 (m, 4H), 7.42-7.00 (m, 24H), 4.79 (d, J=14.6Hz, 2H), 4.64 (s, 2H), 4.57 (d, J=2.5 Hz, 2H), 3.71-2.82 (m, 14 H); ¹³ CNMR (CDCl₃) δ 196.08, 161.84, 139.30, 138.95, 136.89, 134.40, 129.45,129.40, 129.29, 128.92, 128.58, 128.48, 128.02, 127.96, 126.97, 126.54,73.26, 72.29, 71.12, 65.40, 55.82, 32.72; HRMS: calcd. for C₅₁ H₅₁ N₂ O₇: 803.3696; found 803.3693.

Example 15BJ

To a solution of SEM protected imidazole (2 g) in THF (20 mL) was addedt-BuLi (1.7M, 6.9 mL) at -78° C. and the mixture was stirred for 20minutes. After addition of TMSCl (1.25 g), the resulting mixture wasallowed to warm to 0° C. over 2 hours, and then cooled to -78° C. again.The mixture was treated with t-BuLi (1.7M, 6.9 mL), stirred for 20minutes, followed by addition of B(OMe)₃ (10.4 g). The reaction mixturewas warmed to room temperature and stirred overnight. The reaction waspoured into EtOAc/H₂ O and the organic layer was washed to PH 7, driedwith NaSO₄, and purified on column with MeOH to give pureN-SEM-5-borono-imidazole (2.3 g 95%) as a solid. ¹ H NMR (CD₃ OD) δ 7.63(d, J=0.74 Hz, 1H), 6.87 (d, J=1.1 Hz, 1H), 5.47 (s, 2H), 3.55 (t, J=8.4Hz, 2H), 0.93 (t, J=8.4 Hz, 2H), 0.00 (s, 9H); ¹³ C NMR (CD₃ OD) δ138.97, 134.54, 77.89, 68.00, 20.19, 0.00.

A solution of the borono-imidazole prepared above (1.3 g, 5.37 mmol),MEM-protected cpd 12J (0.937 g, 1.01 mmol), Pd(Ph₃ P)₄ (0.18 g, 0.16mmol) and K₂ CO₃ (7.5 g) in THF (20 mL) and H₂ O (20 mL) was degassed,and then was heated to reflux under N₂ overnight. The reaction mixturewas cooled to room temperature and partitioned between EtOAc/H₂ O. Theorganic layer was dried over MgSO₄ and concentrated to give a residue,which was deprotected by general hydrolysis procedures and purified onT.L.C. plate with 5% MeOH in EtOAc to give the coupling product, 15BJ(0.4 g, 37.2%). ¹ H NMR (CD3OD) δ 7.97 (s, 2H), 7.61-7.11 (m, 20H), 5.37(s, 4H), 4.83 (d, J=13.9 Hz, 2H), 3.78-3.73 (m, 4H), 3.59 (t, J=8.0 Hz,4H), 3.18-2.97 (m, 6H), 0.90 (t. J=8.0 Hz, 4H), 0.00 (s, 18H).

Example 15BK

Compound 15BJ was treated with 4M HCl in dioxane under reflux overnight.After the solvent was removed under full vacuum, the residue waspurified on reverse phase T.L.C. plate to give the desired compound as asolid in moderate yield. ¹ H NMR (CD₃ OD) δ 7.71 (sb, 2H), 7.61 (d,J=7.7 Hz, 2H), 7.52 (s, 2H), 7.35-7.19 (m, 10H), 7.10-7.08 (m, 6H), 4.78(d, J=13.9 Hz, 2H), 3.71-3.65 (m, 4H), 3.32-3.00 (m, 4H), 2.96-2.87 (m,2H); ¹³ C NMR (CD₃ OD) δ 163.80, 141.26, 139.94, 137.20, 134.78, 130.67,130.11, 129.52, 128.88, 127.40, 127.08, 125.22, 72.00, 67.72, 57.38,33.60; HRMS: calcd. for C₃₉ H₃₉ N₆ O₃ : 639.3084; found 639.3089.

Example 15BL

Compound 15BK in MeOH was treated with 4M HCl in dioxane and theresulting solvents ware evaporated under full vacuum to give thehydrochloride salt. ¹ H NMR (CD₃ OD) δ 9.02 (d, J=1.1 Hz, 2H), 7.87 (d,J=1.1 Hz, 2H), 7.65-7.38 (m, 8H), 7.19-7.17 (m, 6H), 6.93-6.90 (m, 4H),4.65 (d, J=14.3 Hz, 2H), 3.78-3.72 (m, 4H), 3.25 (d, J=14.3, 2H),3.06-3.02 (m, 2H), 2.81-2.7 (m, 2H); ¹³ C NMR (CD₃ OD) 8163.41, 141.11,141.04, 135.91, 134.97, 131.95, 130.89, 130.51, 129.47, 128.16, 128.10,127.43, 126.09, 116.38, 71.80, 69.21, 57.87, 33.73.

Example 15BM

2-Trimethyltin-N-dimethylsulfamoyl-imidazole was prepared in situ bylithiation of N-dimethylsulfamoyl-imidazole (1.75 g, 10 mmol) in THF (30mL) at -78° C. with n-BuLi (1.6M, 7.5 mL), followed by quenching withtrimethyltin chloride (2.19 g, 11 mmol). A coupling reaction of the tinreagent (1.2 g, crude) and MEM-protected compound 12J (0.8 g, 0.86 mmol)in the presence of Pd(Ph₃ P)₄ (0.18 g, 0.16 mmol) was carried out underreflux overnight. After being cooled to room temperature, the reactionmixture was poured into EtOAc/H₂ O. The organic layer was dried overMgSO₄ and concentrated on a rotary evaporator. The residue was dissolvedin MeOH, saturated with HCl (gas) at 0° C. for 5 minutes and thenstirred at that temperature for 1 hour. The resulting mixture was workedup and purified on column with EtOAc to give compound 15BM as asolid(450 mg, 61%). ¹ H NMR (CD₃ OD) δ 7.61-7.11 (m, 22H), 4.86 (d,J=14.3 Hz, 2H), 3.61-3.59 (m, 4H), 3.10-2.92 (m, 6H), 2.54 (s, 6H); ¹³ CNMR (CD₃ OD) δ 163.98, 148.97, 141.21, 139.37, 132.57, 132.17, 131.55,130.98, 130.69, 129.63, 129.50, 128.30, 127.53, 123.61, 71.92, 66.99,56.66, 38.23, 33.74. HRMS: calcd. for C₄₃ H₄₉ N₈ O₇ S₂ : 853.3166; found853.3163.

Example 15 BN

A solution of 4-iodopyrazole (1.54 g, 8 mmol) in THF (20 mL), wastreated with NaH (4.3 g, 10.6 mmol), followed by quenching withdimethylsulfamoyl chloride (1.38 g, 9.6 mmol) to form the N-protectedpyrazole (2.4 g, 92%). This intermediate (1.5 g, 5 mmol) was reactedwith hexamethylditin (1.8 g, 5.5 mmol) in the presence of Pd(Ph₃ P)₄(0.055 g, 0.01 mmol) in THF (25 mL) at 78° C. overnight to give crude4-trimethyltin-N-dimethylsulfamoyl-pyrazole.

The crude tin compound was reacted with MEM-protected cpd 12J (0.932 g,1.0 mmol) in the presence of Pd(Ph₃ P)₄ (0.18 g, 0.16 mmol) under refluxto form the coupled product, which was deprotected by general hydrolysisprocedure, followed by purification on reverse phase TLC plate with 85%MeOH in water to give compound 15BN as a solid. ¹ H NMR (CD₃ OD) δ7.77-7.12 (m, 4H), 7.38-6.95 (m, 18H), 4.72 (d, J=14.3 Hz, 2H),3.59-3.55 (m, 4H), 3.02-2.88 (m, 6H); ¹³ C NMR (CD₃ OD) δ 163.36,140.63, 139.40, 133.75, 130.19, 129.83, 129.18, 127.87, 127.38, 127.12,125.47, 122.79, 71.64, 66.46, 56.76, 33.23;

Example 15BP

MEM-protected mono-m-bromobenzyl cyclic urea was made by generalprocedure for preparation of monoalkylated cyclic ureas. Themonoalkyated intermediate (2.4 g, 3.56 mmol) was dissolved in DMF (15mL) and treated with NaH (0.43 g, 10.75 mmol), followed by addition ofmethyl m-bromomethylbenzoate (1.63 g, 7.1 mmol) to give pure desiredasymmetric cyclic urea (1.6 g, 55%).

This asymmetric urea (1.6 g, 2 mmol) was coupled with5-borono-N-SEM-pyrazole (0.48 g, 2 mmol) by the same procedure describedfor example 15BJ above to provide pure coupled product, which wasfurther deprotected by general hydrolysis procedure to form compound15BP (0.9 g, 73.2% for the two steps). ¹ H NMR (CD₃ OD) δ 7.85-7.82 (m,2H), 7.66-7.57 (m, 4H), 7.35-7.01 (m, 13H), 6.56 (s, 1H), 4.76 (d,J=14.3 Hz, 1H), 4.69 (d, J=14.3 Hz, 1H), 3.77 (s, 3H), 3.72-3.58 (m,4H), 3.11-3.02 (m, 4H), 2.94-2.84 (m, 2H); ¹³ C NMR (CD₃ OD) δ 166.79,162.24, 139.69. 139.59, 138.56, 138.50, 133.63, 130.09, 129.16, 128.78,128.61, 128.46, 128.29, 128.16, 126.59, 126.08, 124.60, 102.00, 70.50,66.36, 66.31, 55.99, 55.63, 51.32, 32.23, 32.15; LRMS: 631.4 (M+1,100%); HRMS: calcd. for C₃₈ H₃₉ N₄ O₅ : 631.2920; found 631.2916.

Example 15BQ

To a solution of compound 15BP (63 mg, 0.1 mmol) in THF (1 mL) was addedLiBH₄ (2M in THF, 0.3 mL) and MeOH (57.6 mg, 1.8 mmol) and the resultingmixture was stirred at room temperature overnight. The mixture wasacidified to pH 1 with 2N HCl and extracted with EtOAc. The organiclayer was washed with H₂ O, brine, dried over MgSO₄, and concentrated.The residue was purified on TLC plate with EtOAc to give the desiredcompound (46 mg, 76.3%). ¹ H NMR (CD₃ OD) δ 7.78-7.60 (m, 4H), 7.50-7.07(m, 15H), 6.68 (d, J=2.2 Hz, 1H), 4.90-4.81 (m, 2H), 4.66 (bs, 2H),3.79-3.63 (m, 4H), 3.18-3.00 (m, 6H); ¹³ C NMR (CD₃ OD) δ 163.92,143.24, 141.32, 141.23, 139.41, 130.67, 130.17, 129.93, 129.69, 129.57,129.53, 129.30, 129.04, 128.04, 127.45, 127.41, 127.25, 126.01, 103.33,72.02, 71.96, 67.04, 64.97, 57.30, 57.07, 33.63, 33.57; LRMS: 603.2(M+1, 100%); HRMS: calcd. for C₃₇ H₃₉ N₄ O₄ : 603.291; found 603.2968.

Example 15BR

N-dimethylsulfamoyl-imidaz-2-yl zinc chloride was prepared in situ bylithiation of N-dimethylsulfamoylimidazole (0.97 g, 5.5 mmol) in THF (20mL) with t-BuLi (1.7M, 6.7 mL), followed by quenching with zinc chloride(1.87 g, 13.75 mmol).

A coupling reaction of the zinc reagent (crude) and MEM-protected cpd12J (0.932 g, 1.0 mmol) in the presence of Pd(Ph₃ P)₄ (0.12 g, 0.1 mmol)was carried out under reflux overnight. After cooling to roomtemperature, the reaction mixture was poured into EtOAc/H₂ O. Theorganic layer was dried over MgSO₄ and concentrated on a rotaryevaporator. The residue was dissolved in MeOH, and treated with 4M HClin dioxane under reflux for 2 hours. The resulting mixture was worked upand purified on a reverse phase TLC plate with 75% MeOH in water to givecompound 15BR as a solid. ¹ H NMR (CD₃ OD) δ 7.75-7.70 (m, 4H),7.42-7.33 (m, 2H), 7.28-7.12 (m, 12H), 7.00-6.94 (m, 4H), 4.73 (d,J=14.3 Hz, 2H), 3.71 (bs, 4H), 3.14 (d, J=13.9 Hz, 2H), 3.04-2.99 (m,2H), 2.85-2.77 (m, 2H); ¹³ C NMR (CD₃ OD) δ 162.00, 146.27, 139.58,138.87, 130.23, 129.36, 129.11, 128.80, 128.00, 126.20, 125.89, 124.36,122.64, 70.39, 67.14, 56.29, 32.22; HRMS: calcd. for C₃₉ H₃₉ N₆ O₃ :639.3084; found 639.3069.

Example 15BS

Compound 15BR was dissolved in MeOH, and treated with 4M HCl in dioxaneat r.t. for 1 minute. The resulting mixture was concentrated in vacuo togive the solid dihydrochloride salt. ¹ H NMR (CD₃ OD) δ 7.81-7.79 (m,2H), 7.73 (s, 2H), 7.65 (s, 4H), 7.61-7.57 (m, 4H), 7.13-7.11 (m, 6H),6.86-6.84 (m, 4H), 4.59 (d, J=13.9 Hz, 2H), 3.84 (s, 2H), 3.76 (d,J=11.7 Hz, 2H), 3.45 (d, J=14.1 Hz, 2H), 3.06 (d, J=12.2 Hz, 2H),2.75-2.68 (m, 2H); ¹³ C NMR (CD₃ OD) δ 163.39, 145.94, 141.63, 140.94,134.79, 131.28, 130,46, 129.44, 129.13, 127.38, 127.14, 124.31, 121.37,71.58, 69.54, 57.82, 33.84.

Example 15BT

To compound 15BP (63 mg, 0.1 mmol) was added 4-(2-aminoethyl)morpholine(0.13 g, 1 mmol) and the resulting mixture was stirred at 110° C.overnight. The mixture was evaporated in vacuo to remove the excess4-(2-aminoethyl)morpholine, and the residue was purified on TLC platewith 10% MeOH in EtOAc to give pure product (44 mg, 60.4%). ¹ H NMR (CD₃OD) δ 8.04 (s, 1H), 7.73-6.99 (m, 18H), 6.59 (d, J=2.2 Hz, 1H), 4.72 (d,J=14.4 Hz, 2H), 3.69-3.64 (m, 8H), 3.36 (t, J=6.6 Hz, 2H), 3.14 (J=14.2Hz, 2H), 3.08-2.85 (m, 4H), 2.54 (t, J=6.6 Hz, 2H), 2.51-2.45 (m, 4H);¹³ C NMR (CD₃ OD) δ 169.84, 163.68, 141.25, 141.12, 140.09, 136.07,133.65, 130.63, 129.87, 129.56, 129.51, 128.02, 127.44, 103.31, 71.98,71,91, 68.26, 67.75, 58.62, 58.37, 58.45, 54.68, 37.76, 35.76, 33.69,33.62; HRMS: calcd. for C₄₃ H₄₉ N₆ O₅ : 729.3764; found 729.3753.

Example 15BU

MEM-protected mono-m-bromobenzyl cyclic urea was made by generalprocedure for preparation of monoalkylated cyclic ureas. The mono cyclicurea (2.4 g, 3.56 mmol) in DMF (15 mL) was coupled with5-borono-N-SEM-pyrazole by the same procedure used to make compound 20AXto provide pure coupled product, MEM-protected monom-(N-SEM-pyraz-5-yl)benzyl cyclic urea.

This intermediate (0.2 g, 0.25 mmol) in DMF (5 mL) was treated with NaH(0.04 g, 1.0 mmol), followed by quenching with m-picolyl chloridehydrochloride (0.123 g, 0.75 mmol) to give desired asymmetric cyclicurea, which was further deprotected by general hydrolysis procedure toform compound 15BU. ¹ H NMR (CD₃ OD) δ 8.51-8.46 (m, 2H), 7.83-7.63 (m,4H), 7.48-7.03 (m, 13H), 6.68 (d, J=2.2 Hz, 1H), 4.84 (d, J=14.3 Hz,1H), 4.66 (d, J=14.3 Hz, 1H), 3.85-3.76 (m, 4H), 3.20-2.83 (m, 6H); ¹³ CNMR (CD₃ OD) δ 163.63, 151.12, 149.22, 141.12, 141.07, 139.41, 135.98,130.60, 130.55, 130.24, 129.63, 129.60, 128.04, 127.54, 126.08, 125.34,103.35, 71.94, 71.81, 68.72, 55.13, 33.75, 33.61; HRMS: calcd. for C₃₅H₃₆ N₅ O₃ : 574.2818; found 574.2811.

Example 15BV

The MEM-protected mono m-(N-SEM-pyraz-5-yl)-benzyl cyclic urea (788 mg,1 mmol), described in procedure of example 15U was dissolved in DMF (8mL) and treated with NaH (0.16 g, 4.0 mmol, 60% in mineral oil),followed by quenching with α-bromo-m-tolunitrile (0.392 g, 2.0 mmol) togive desired asymmetric cyclic urea, which was further deprotected bygeneral hydrolysis procedure to form compound 15BV. ¹ H NMR (CD₃ OD) δ7.99-7.07 (m, 19H), 6.68 (bs, 1H), 4.70 (d, J=13.9 Hz, 1H), 4.64 (d,J=13.9 Hz, 1H), 3.93-3.70 (m, 4H), 3.21-2.83 (m, 6H); ¹³ C NMR (CD₃ OD)δ 163.82, 141.40, 141.24, 141.14, 135.42, 134.42, 133.90, 132.52,130.85, 130.67, 130.15, 130.03, 129.82, 129.71, 128.16, 127.66, 119.67,113.62, 103.40, 71.92, 71.87, 68.67, 57.14, 33.79, 33.62; HRMS: calcd.for C₃₇ H₃₆ N₅ O₃ : 598.2818; found 598.2813.

Example 15BW

To a solution of compound 15BV (50 mg, 0.084 mmol) in pyridine (3 mL)was added hydroxylamine hydrochloride (36 mg, 5.2 mmol) and theresulting mixture was refluxed overnight. After being cooled to roomtemperature, the mixture was evaporated in vacuo to remove pyridine. Theresulting residue was worked up and purified on TLC plate with EtOAc togive pure amidoxime (32 mg, 60.6%). ¹ H NMR (CD₃ OD) δ 7.96-7.05 (m,19H), 6.59 (d, J=2.2 Hz, 1H), 4.78 (d, J=14.3 Hz, 1H), 4.75 (d, J=14.3Hz, 1H), 3.70-3.59 (m, 4H), 3.11-3.03 (m, 4H), 2.96-2.88 (m, 2H); ¹³ CNMR (CD₃ OD) δ 163.82, 141.25, 141.14, 140.02, 139.77, 134.52, 134.00,131.68, 130.62, 130.18, 129.93, 129.69, 129.56, 129.54, 128.04, 127.44,126.01, 103.32, 71.97, 67.65, 67.58, 57.31, 56.97, 33.67, 33.56.

Example 15BX

Mono-m-(N-SEM-pyraz-5-yl)-benzyl cyclic urea prepared above in procedureof Example 15BU was deprotected by general hydrolysis procedure to givecompound XS618. ¹ H NMR (CD₃ OD) δ 7.67-7.05 (M, 15H), 6.58 (d, J=4.0Hz, 1H), 4.80 (d, J=14.7 Hz, 1H), 3.86-3.82 (m, 1H), 3.71-3.62 (m, 2H),3.51-3.48 (m, 1H), 3.18-2.99 (m, 4H), 2.80-2.72 (m, 1H); ¹³ C NMR (CD₃OD) δ 163.90, 141.47, 140.89, 130.63, 130.49, 130.09, 130.01, 129.64,129.49, 129.27, 127.52, 127.25, 125.85, 103.33, 72.99, 72.55, 66.50,66.47, 55.27, 35.13, 34.32; HRMS: calcd. for C₂₉ H₃₁ N₄ O₃ : 483.2400;found 483.2401.

Example 15BY

MEM-protected mono m-(N-SEM-pyraz-5-yl)benzyl cyclic urea describedabove (220 mg, 0.28 mmol) was dissolved in DMF (3 mL) and treated withNaH (0.045 g, 1.12 mmol, 60% in mineral oil), followed by quenching withp-benzyloxybenzyl chloride (0.13 g, 0.56 mmol) to give the desiredasymmetric cyclic urea, which was deprotected by general hydrolysisprocedure to give compound 15BY. ¹ H NMR (CD₃ OD) δ 7.68-6.91 (m, 24H),6.58 (d, J=2.2 Hz, 1H), 5.02 (s, 2H), 4.78 (d, J=13.9 Hz, ¹ H), 4.66 (d,J=13.9 Hz, 1H), 3.67-3.54 (m, 4H), 3.08-2.88 (m, 6H); ¹³ C NMR (CD₃ OD)δ 163.88, 159.84, 141.29, 138.63, 131.73, 131.58, 130.69, 130.64,130.15, 129.56, 129.49, 129.46, 128.82, 128.50, 128.03, 127.46, 127.37,125.99, 116.07, 103.32, 72.05, 72.02, 66.81, 56.45, 33.62, 33.59; HRMS:calcd. for C₄₃ H₄₃ N₄ O₄ : 6779.3284; found 679.3284.

Example 15BZ

To compound 15BP (45 mg, 0.071 mmol) was added 3-(aminomethyl)pyridine(0.077 g, 0.71 mmol) and the resulting mixture was stirred at 110° C.overnight. The mixture was evaporated in vacuo to remove the excess3-(aminomethyl)-pyridine. The residue was purified on TLC plate with 15%MeOH in EtOAc to give pure product (37 mg, 73.8%). ¹ H NMR (CD₃ OD) δ7.80-6.95 (m, 23 H), 6.59 (d, J=2.2 Hz, 1H), 4.77-4.72 (m, 1H), 4.68 (d,J=14.3 Hz, 1H), 4.58 (d, J=2.2 Hz, 2H), 3.66-3.64 (m, 4H), 3.15 (d,J=14.3 Hz, 1H), 3.06-2.82 (m, 5H); ¹³ C NMR (CD₃ OD) δ 170.09, 163.83,152.96, 149.63, 141.32, 141.23, 140.30, 137.40, 136.94, 135.80, 134.04,130.71, 130.29, 130.09, 129.75, 129.66, 128.12, 127.67, 127.54, 126.14,125.34, 125.19, 103.38, 72.00, 71.93, 68.47, 57.56, 42.02, 33.62.

Example 15AC

Hydrogenation of compound 15BY in MeOH in the presence of catalyticamount of 10% Pd/C produced the hydroxymethyl compound in good yield. ¹H NMR (CD₃ OD) δ 7.68-7.58 (m, 3H), 7.39-7.05 (m, 12H), 6.98 (d, J=8.4Hz, 2H), 6.73 (d, J=8.4 Hz, 2H), 6.58 (d, J=2.2 Hz, 1H), 4.78 (d, J=14.3Hz, 1H), 4.66 (d, J=13.9 Hz, 1H), 3.68-3.50 (m, 4H), 3.08-2.83 (m, 6H);¹³ C NMR (CD₃ OD) δ 163.94, 158.15, 141.31, 140.11, 131.73, 130.69,130.65, 130.16, 129.96, 129.56, 129.48, 128.04, 127.46, 127.35, 125.98,116.39, 103.32, 72.10, 72.02, 66.42, 57.22, 56.37, 33.56; HRMS: calcd.for C₃₆ H₃₇ N₄ O₄ : 589.2815; found 589.2811.

Example 15BC

To compound 15BP (44 mg, 0.07 mmol) was added 2-(aminomethyl)pyridine(0.077 g, 0.71 mmol) and the resulting mixture was stirred at 110° C.overnight. The mixture was evaporated in vacuo to remove the excess2-(aminomethyl)pyridine. The residue was purified on a TLC plate with20% MeOH in EtOAc to give pure product (35 mg, 71%). ¹ H NMR (CD₃ OD) δ8.45 (d, J=4.8 Hz, 1H), 7.80-6.98 (m, 22H), 6.58 (d, J=1.5 Hz, 1H), 4.77(d, J=14.3 Hz, 1H), 4.71 (d, J=14.3 Hz, 1H), 4.66 (d, J=4.8 Hz, 2H),3.68-3.65 (m, 4H), 3.17-2.82 (m, 6H); ¹³ C NMR (CD₃ OD) δ 169.99,163.71, 159.28, 149.75, 141.25, 141.14, 140.17, 139.98, 138.80, 135.79,133.94, 130.63, 130.18, 129.96, 129.92, 129.57, 128.03, 127.64, 127.45,126.03, 123.72, 122.76, 103.32, 71.99, 71.92, 68.32, 67.72, 57.50,57.30, 45.92, 33.69, 33.65; HRMS: calcd. for C₄₃ H₄₃ N₆ O₄ : 707.3346;found 707.3344.

Example 15CC

MEM-protected mono m-(N-SEM-pyraz-5-yl)benzyl cyclic urea (200 mg, 0.254mmol) was dissolved in DMF (5 mL) and treated with NaH (0.041 g, 1.02mmol, 60% in mineral oil), followed by quenching withm,p-dibenzyloxybenzyl chloride (0.172 g, 0.51 mmol) to give the desiredasymmetric cyclic urea. After deprotection by general hydrolysisprocedure, the urea was hydrogenated to give the dihydroxy compound. ¹ HNMR (CD₃ OD) δ 7.83-7.07 (m, 15H), 6.81-6.71 (m, 3H), 6.53 (s, 1H), 4.86(d, J=13.9 Hz, 1H), 4.72 (d, J=13.6 Hz, 1H), 3.80-3.66 (m, 4H),3.19-2.82 (m, 6H); ¹³ C NMR (CD₃ OD) δ 164.10, 149.97, 146.56, 146.12,141.43, 141.32, 140.29, 134.53, 133.55, 130.82, 130.71, 130.67, 130.29,129.64, 129.53, 128.23, 127.51, 127.42, 126.14, 122.22, 117.49, 116.39,103.59, 72.13, 72.01, 67.77, 65.89, 57.28, 56.35, 33.61, 33.45; HRMS:calcd. for C₃₆ H₃₇ N₄ O₅ : 605.2764; found 605.2750.

Example 15CD

MEM-protected mono m-(N-SEM-pyraz-5-yl)-benzyl cyclic urea (560 mg, 0.71mmol) was dissolved in DMF (10 mL) was treated with NaH (0.114 g, 2.84mmol, 60% in mineral oil), followed by quenching of m-nitrobenzylchloride (0.360 g, 2.13 mmol) to give desired asymmetric cyclic urea.After deprotection by general de-MEM procedure, the urea was purified onTLC plate with EtOAc to give pure product. ¹ H NMR (CD₃ OD) δ 8.11-8.06(m, 2H), 7.69-7.15 (m, 13H), 7.06-6.95 (m, 4H), 6.59 (d, J=2.2 Hz, 1H),4.76 (d, J=13.9 Hz, 1H), 4.61 (d, J=14.3 Hz, 1H), 3.78-3.56 (m, 4H),3.15-2.79 (m, 6H); ¹³ C NMR (CD₃ OD) δ 163.75, 149.67, 141.75, 141.12,140.97, 136.71, 130.78, 130.53, 130.21, 129.93, 129.73, 129.57, 128.04,127.53, 127.43, 126.07, 125.37, 123.51, 103.33, 71.84, 68.28, 57.31,56.86, 33.85, 33.58; HRMS: calcd. for C₃₆ H₃₆ N₅ O₅ : 618.2716; found618.2703.

Example 15CE

Hydrogenation of compound 15CD (210 mg, 0.34 mmol) in MeOH (5 mL) and 1NHCl (1 mL) in the presence of 10% Pd/C was carried out at roomtemperature overnight. The catalyst was removed by filtration, and thefiltrate was concentrated. The residue was purified on TLC plate withEtOAc to give the amino compound (140 mg, 61%). ¹ H NMR (CD₃ OD) δ 8.31(s, 1H), 7.81-6.88 (m, 19H), 4.60 (d, J=13.6 Hz, 2H), 3.80-3.57 (m, 4H),3.16-2.68 (m, 6H); ¹³ C NMR (CD₃ OD) δ 163.99, 149.09, 141.38, 141.23,140.01, 130.73, 130.65, 130.35, 130.15, 129.93, 129.55, 129.46, 128.04,127.42, 127.35, 125.97, 120.06, 117.33, 115.81, 103.32, 72.11, 71.99,66.39, 57.28, 56.97, 33.66, 33.53; HRMS: calcd. for C₃₆ H₃₈ N₅ O₃ :588.2975; found 588.2983.

Example 15CF

MEM-protected mono m-(N-SEM-pyraz-5-yl)-benzyl cyclic urea (240 mg, 0.3mmol) was dissolved in DMF (5 mL) and treated with NaH (0.049 g, 1.2mmol, 60% in mineral oil), followed by addition ofm-cyano-p-fluorobenzyl bromide (0.128 g, 0.6 mmol) to give desiredasymmetric cyclic urea. After deprotection by general hydrolysisprocedure, the urea was purified on TLC plate with EtOAc to give purecompound 15CF (72 mg, 39%). ¹ H NMR (CD₃ OD) δ 7.68-6.86 (m, 18H), 6.57(d, J=0.7 Hz, 1H), 4.72 (d, J=14.1 Hz, 1H), 4.36 (d, J=13.8 Hz, 1H),3.82-3.55 (m, 4H), 3.16-2.69 (m, 6H); HRMS: calcd. for C₃₇ H₃₅ N₅ O₃ F:616.2713; found 616.2710.

Example 15CG

A solution of compound 15BX in MeOH was treated with 4M HCl in dioxane,and the resulting solution was evaporated to dryness in vacuo to givethe hydrochloride salt. ¹ H NMR (CD₃ OD) δ 8.31 (d, J=2.6 Hz, 1H),7.72-7.06 (m, 15H), 4.68 (d, J=15 Hz, 1H), 3.83-3.75 (m, 3H), 3.73-3.60(m, 1H), 3.59-3.41 (m, 1H), 3.23-3.03 (m, 3H), 2.69-2.65 (m, 1H); ¹³ CNMR (CD₃ OD) δ 163.52, 148.75, 141.15, 140.30, 136.47. 132.50, 130.88,130.49, 130.35, 129.62, 129.46, 128.32, 127.53, 127.35, 127.04, 106.27,73.14, 72.49, 67.06, 58.97, 55.16, 35.61, 34.93.

Example 15GH

A solution of the compound of Example 9P (0.11 g, 0.2 mmol) andhydroxylamine hydrochloride (0.014 mg, 0.2 mmol) in pyridine (2 mL) wasrefluxed overnight. Workup and purification using HPLC with a solventgradient from 10% hexane in EtOH to 100% of EtOH provided compound 15GH(28 mg). ¹ H NMR (CD₃ OD) δ 7.89-7.86 (m, 1H), 7.81 (s, 1H), 7.54 (d,J=4.0 Hz, 1H), 7.45-7.00 (m, 15H), 4.73 (d, J=14.1 Hz, 1H), 4.71 (d,J=14.2 Hz, 1H), 3.62-3.55 (m, 4H), 3.17 (d, J=14.2 Hz, 1H), 3.08-3.05(m, 2H), 2.98 (d, J=14.1 Hz, 1H), 2.96-2.83 (m, 2H), 2.54 (s, 3H), 2.16(s, 3H); ¹³ C NMR (CD₃ OD) δ 200.03, 163.85, 155.42, 141.19, 141.16,140.19, 139.40, 139.00, 138.63, 135.31, 130.77, 130.62, 130.59, 130.48,130.07, 129.71, 129.60, 129.57, 128.71, 128.11, 127.50, 126.35, 71.99,71.93, 67.81, 67.24, 57.15, 57.09, 33.65, 26.72, 11.94; HRMS: calcd. forC₃₇ H₄₀ N₃ O₅ : 606.2968; found 606.2971.

Examples 15CI and 15CJ

Bis-m-cyano-p-fluorobenzyl cyclic urea was prepared using generalalkylation and deprotection procedures. The urea (0.47 g, 0.79 mmol) inTHF (20 mL) was treated with MeMgBr (3M, 2.5 mL, 0.5 mmol) under refluxfor 3 hours. General workup and purification on TLC plate with 40% EtOAcin CH₂ Cl₂, followed by further purification on HPLC with 85% hexane inEtOH gave compound 15CI (40 mg) and compound 15CJ (80 mg).

Example 15CI: ¹ H NMR (CDCl₃) δ 7.64 (dd, J=7.0 Hz, J=2.2 Hz, 2H),7.40-7.00 (m, 14H), 4.72 (dd, J=14.6 Hz, 2H), 3.75 (s, 2H), 3.55 (d,J=11.4 Hz, 2H), 3.22 (d, J=14.6 Hz, 2H), 3.08 (dd, J=13.6 Hz, J=2.6 Hz,2H), 2.83 (dd, J=13.2 Hz, J=11.0 Hz, 2H), 2.59 (d, J=4.8 Hz, 6H), 2.51(b, 2H); ¹³ C NMR (CDCl₃) δ 196.31 (d, J=3.1 Hz), 161.71, 161.46 (d,J=255.6 Hz), 139.39, 135.78 (d, J=9.2 Hz), 134.74, 130.82 (d, J=2.3 Hz),129.31, 128.60, 126.48, 125.38 (d, J=13.0 Hz), 116.97 (d, J=14.4 Hz),70.89, 65.58, 55.08, 32.78, 31.26 (d, J=7.6 Hz); HRMS: calcd. for C₃₇H₃₇ N₂ O₅ F₂ : 627.2671; found 62.2670.

Example 15CJ: ¹ H NMR (CDCl₃) 7.74 (dd, J=7.0 Hz, J=2.2 Hz, 2H),7.57-7.00 (m, 14H), 4.80 (d, J=14.3 Hz, 1H), 4.62 (d, J=14.3 Hz, 1H),3.90 (bs, 2H), 3.71-3.61 (m, 2H), 3.53 (d, J=14.6 Hz, 1H), 3.29 (d,J=14.3 Hz, 1H), 3.25-3.17 (m, 4H), 2.93-2.82 (m, 2H), 2.68 (s, 3H), 2.66(s, 3H); ¹³ C NMR (CDCl₃) δ 196.48 (d, J=2.3 Hz), 162.37 (d, J=259.4Hz), 161.75, 161.58 (d, J=255.6 Hz), 139.21, 139.15, 136.02 (d, J=8.4Hz), 135.85 (d, J=8.4 Hz), 135.34 (d, J=3.8 Hz), 134.62 (d, J=3.0 Hz),134.31, 130.76, 129.24, 128.68, 128.62, 126.63, 126.59, 125.42 (d,J=13.0 Hz), 117.03 (d, J=14.4 Hz), 116.41 (d, J=19.9 Hz), 113.67, 101.28(d, J=15.3 Hz), 70.85, 65.96, 65.75, 55.09, 54.95, 32.96, 32.79, 31.25(d, J=6.9 Hz); HRMS: calcd. for C₃₆ H₃₄ N₃ O₄ F₂ : 610.2517; found610.2534.

Example 15CK

In the synthesis of compound 9Q, compound 15CK was a minor stereoisomerand was isolated on HPLC with 80% hexane in EtOH. ¹ H NMR (CD₃ OD) δ7.55-7.53 (m, 2H), 7.48 (s, 2H), 7.33-7.14 (m, 10H), 7.10-7.07 (m, 4H),4.75 (d, J=14.6 Hz, 2H), 3.61-3.58 (m, 4H), 3.08-3.04 (m, 2H), 2.99 (d,J=14.3 Hz, 2H), 2.96-2.90 (m, 2H), 2.17 (s, 6H); ¹³ C NMR (CD₃ OD) δ163.94, 155.44, 141.22, 139.43, 138.96, 130.76, 130.63, 129.68, 129.56,128.09, 127.46, 126.30, 72.00, 67.09, 57.03, 33.59, 11.97; HRMS: calcd.for C₃₇ H₄₁ N₄ O₅ : 621.3077; found 620.3091.

Example 15CL

By the same procedure used to make Example 9Q, compound 15CL wasobtained from compound 15CI in good yield. ¹ H NMR (CD₃ OD) δ 7.31-7.02(m, 16H), 4.63 (d, J=13.9 Hz, 2H), 3.62-3.56 (m, 4H), 3.09-2.99 (m, 4H),2.90-2.82 (m, 2H), 2.16 (d, J=2.2 Hz, 6H); ¹³ C NMR (CD₃ OD) δ 163.76,161.28 (d, J=248.7 Hz), 153.70, 141.18, 135.44 (d, J=3.8 Hz), 132.57 (d,J=8.4 Hz), 131.86 (d, J=3.8 Hz), 130.60, 129.59, 127.49, 127.13 (d,J=13.7 Hz), 117.21 (d, J=22.9 Hz), 71.90, 67.41, 56.34, 33.66, 14.8 (d,J=4.6 Hz); HRMS: calcd. for C₃₇ H₃₉ N₄ O₅ F₂ : 657.2889; found 657.2874.

Example 15CM

Compound 15CM was obtained from compound XS534 by the same procedureused to make Example 9Q. ¹ H NMR (CD₃ OD) δ 7.34-7.02 (m, 16H), 4.66 (d,J=14.2 Hz, 1H), 4.64 (d, J=14.2 Hz, 1H), 3.64-3.54 (m, 4H), 3.09-2.83(m, 6H), 2.15 (d, J=2.4 Hz, 3H); ¹³ C NMR (CD₃ OD) δ 163.83, 161.29 (d,J=248.0 Hz), 161.08 (d, J=250.3 Hz), 153.67, 151.69, 141.21, 141.16,135.44, 133.40 (d, J=9.2 Hz), 132.58 (d, J=8.4 Hz), 132.20, 131.98 (d,J=3.8 Hz), 130.61, 129.63, 127.49, 127.14 (d, J=13.7 Hz), 122.37 (d,J=13.77 Hz), 117.43 (d, J=22.9 Hz), 117.20 (d, J=22.9 Hz), 71.84, 67.41,66.99, 56.38, 56.98, 33.74, 33.58, 14.78 (d, J=5.3 Hz); HRMS: calcd. forC₃₆ H₃₈ N₅ O₅ F₂ : 658.2841; found 658.2838.

Example 15FN

To a stirred solution of 3.66 g(10 mmol) of compound XXVIIIf in 15 mL ofDMF and 7 mL of THF, cooled to 0° C., was added 1.2 g(40 mmol) of an 80%dispersion of sodium hydride in mineral oil. The mixture was stirred 5min., and 4.66 g(40 mmol) of 3-furylmethylchloride was added. Themixture was warmed to ambient temperature over 30 min. and then recooledto 0° C. The reaction was quenched by the addition of 0.4N HCl, and theresulting mixture was extracted with Et₂ O. The organic extract waswashed with sat'd aq. NaHCO₃, then brine, dried (MgSO₄), andconcentrated under reduced pressure to afford 4.92 g(93%) of alkylatedintermediate. ¹ H NMR (CDCl₃) δ 7.11-7.42(m, 7H); 6.32(s, 1H); 4.72(d,1H); 3.88(s, 1H); 3.82(m, 1H); 3.03(d, 1H); 2.79-2.97(m, 2H); 1.40(s,6H).

To 0.20 g(0.38 mmol) of acetonide protected bis(N-3-furylmethyl cyclicurea above was added 8 mL of MeOH and 1 mL of conc. aq. HCl. Thesolution was stirred 1 h at ambient temperature and poured into water.The white colloidal suspension was extracted with 1:1 Et₂ O-EtOAc, andthe organic extract was washed with sat'd aq. NaHCO₃, brine, dried(MgSO₄), and concentrated under reduced pressure to afford an off-whitesolid. This material was dissolved in 7 mL of EtOAc and warmed toboiling. Hexane, 20 mL, was introduced, and the solution wasconcentrated to ˜6 mL. The product was triturated with 3 mL of hexanesand allowed to cool. Solvent was removed by pipette, and the whitecrystalline solid was washed with 9:1 hexanes-EtOAc. The diol 15FN,following removal of residual solvent at vacuum pump pressure, weighedlllmg (60% of theoretical).

Example 15FO

To 0.22 mL (2.3 mmol) of stirred, cooled POCl₃ was added 0.20 mL (2.5mmol) of DMF. The solution was stirred 5 min., and a solution of 530 mg(1.0 mmol) of acetonide protected bis(N-3-furylmethyl)cyclic urea,described in example 15FN above, in 0.5 mL of THF and 0.5 mL of DMF wasintroduced. The solution was warmed to ambient temperature with stirringover 25 min., whereupon an additional 0.10 mL of POCl.sub.₃ wasintroduced. The reaction was heated to reflux for 30 min., cooled, andpoured into water. The resulting colloidal solid was extracted with 1:1Et₂ O-EtOAc, and the organic extract was washed with sat'd aq. NaHCO₃,water, then brine. Drying (MgSO₄), and concentration under reducedpressure afforded a brown oil. Chromatography on silica gel (gradientelution with 3:1 to 1:1 hexanes-EtOAc) afforded 120 mg (22%) ofmonoaldehyde intermediate as an oil. ¹ H NMR (CDCl₃) δ 9.41(s, 1H, CHO);7.52(s, 1H, furyl); 7.00-7.38(m, 12H, aryl); 6.59(s, 1H, furyl); 6.31(s,1H, furyl); 4.80(d, 1H, J=14.6 Hz, one of NCH₂); 4.69(d, 1H, J=14.6 Hz,NCH₂); 3.77-4.03(m, 5H, 2×Hα, one of NCH₂, CHOC(CH₃)₂ OCH); 2.68-302(m,5H, one of NCH₂, 4×Hβ); 1.44(s, 3H, CH₃); 1.42(s, 3H, CH₃).

To a stirred solution of 100 mg (0.18 mmol) of the monoaldehydeintermediate in 10 mL of MeOH and 1 mL of water was added 0.5 mL ofconc. aq. HCl. The solution was stirred for 1 h at ambient temperature,poured into water, and extracted with 1:1 Et₂ O-EtOAc. The organicextract was washed with brine, dried (MgSO₄), and concentrated underreduced pressure to afford diol 15FO as an oil. ¹ H NMR (CDCl₃) δ9.43(s, 1H); 7.51(s, 1H); 6.98-7.36(m, 12H); 6.64(s, 1H); 6.32(s, 1H);4.73(d, 1H, J=15 Hz); 4.64(d, 1H, J=15 Hz); 3.55-3.78(m, 5H);2.62-3.14(m, 6H).

Example 15FP

To a stirred solution of 530 mg (1.00 mmol) of acetonide protectedbis(N-3-furylmethyl cyclic urea, described in example 15FN above, in 8mL of THF, cooled to -78° C., was added 1.6 mL (2.5 mmol) of a 1.6Msolution of n-BuLi in THF. The solution was stirred 20 min. at -78° C.,and DMF was added. The reaction was stirred 1 h at -78° C., whereupon itwas quenched with 1N HCl. The mixture was extracted with Et₂ O, and theorganic extract was washed with brine, dried(MgSO₄), and concentratedunder reduced pressure. Chromatography on silica gel (elution with 1:1EtOAc-hexanes) afforded, after removal of solvent, 310 mg (53%) ofdialdehyde intermediate as an oil. ¹ H NMR (CDCl₃) δ 9.42(s, 1H);7.52(d, 1H, J=2 Hz); 7.20-7.36(m, 5H); 6.58(d, 1H, J=2H); 4.18(ABq, 2H,J_(AB) =13 Hz, Δν=330 Hz); 4.00(br. s, 1H); 3.90(d, 1H, J=11 Hz);2.84(ABx, 2H, J_(AB) =13.5 Hz, J_(AX) =1.7 Hz, J_(BX) =11.3 Hz, Δν=78Hz); 1.45(s, 6H).

To a stirred, cooled (-78° C.) solution of 120 mg (0.21 mmol) of thedialdehyde intermediate in 4 mL of Et₂ O was added 2 mL (2 mmol) of 1Mdiisobutylaluminum hydride in CH₂ Cl₂. The solution was stirred 15 minat -78° C., the dry ice bath was removed, and the reaction was quenchedwith saturated aqueous sodium potassium tartrate. The mixture wasdiluted with Et₂ O, and the two phases were stirred together for 30 min.The phases were separated, and the organic phase was dried (MgSO₄),concentrated, and chromatographed on silica gel. The product was elutedwith EtOAc, concentrated, and re-dissolved in 8 mL of MeOH. Thissolution was treated with 0.4 mL of con. aq. HCl, stirred 1 h, andpoured into water. The colloidal suspension was extracted with EtOAc,and the organic extract was washed with brine, dried (MgSO₄), andconcentrated under reduced pressure. Chromatography on silica gel(elution with EtOAc) afforded a glass which was lyophilized frombenzene-acetonitrile to give 62 mg (57%) of tetraol 15FP as a powder. ¹H NMR (CD₃ OD) δ 7.43(d, 1H, J=2 Hz); 7.20-7.37(m, 3H); 7.11(dd, 2H,J=8.1, 1.1 Hz); 6.37(d, 1H, J=2H); 4.22(ABq, 2H, J_(AB) =13.3 Hz, Δν=33Hz); 3.76(ABq, 2H, J=14.6 Hz, Δν=460 Hz); 3.65(br. s, 1H); 3.56(br. d,1H, J=11 Hz); 2.98(ABx, 2H, J_(AB) =13.3 Hz, J_(AX) =1.8 Hz, J_(BX)=12.1 Hz, Δν=54 Hz). Mass spec. (NH₃ --CI/DDIP): 529((M+H--H₂ O)⁺,100%).

Example 15FQ

To a stirred solution of 55 mg (0.1 mmol) of monoaldehyde intermediateprepared in example 15FO in 2 mL of EtOH and 1 mL of water was added 35mg (0.5 mmol) of hydroxylamine hydrochloride. The solution was stirred25 h at ambient temperature, poured into water, and extracted withEtOAc. The organic extract was washed with brine, dried (MgSO₄), andconcentrated under reduced pressure to afford 33 mg (58%) of oxime 15FQas an amorphous solid. Mass Spec.(NH₃ --CI/DDIP): 530((M+H)⁺, 8%);512((M+H--H₂ O)⁺, 100%). ¹ H NMR (CDCl₃) δ 7.76(s, 1H); 7.01-7.38(m,13H); 6.47(s, 1H); 6.32(s, 1H); 4.59-4.76(m, 2H); 3.55-3.84(m, 4H);3.25(d, 1H, J=15 Hz); 2.75-3.09(m, 5H).

Example 15FR

c.) To a stirred solution of 50 mg (0.097 mmol) of compound of example15FO in 6 mL of EtOH was added 20 mg (excess) sodium borohydride. Thesolution was stirred 3 h at ambient temperature, kept at -23° C. for 15h, and rewarmed to ambient temperature with stirring over 6 h. Thereaction was quenched with 10% aq. HOAc, stirred for 30 min., andextracted with EtOAc. The organic extract was washed with brine, dried(MgSO4), and concentrated under reduced pressure. Chromatography onsilica gel (elution with EtOAc) followed by lyophilization afforded 45mg (90%) of triol 15FR as a white powder. ¹ H NMR (CDCl₃) δ 7.05-7.38(m,11H); 6.85(s, 1H); 6.82(s, 1H); 6.30(s, 2H); 4.51-4.61(m, 2H); 4.31(d,1H, J=13 Hz); 3.93(dd, J=14, 5 Hz); 3.65-3.77(m, 2H)3.51-3.60(m, 1H);2.74-3.12(m, 6H). Mass Spec.(NH₃ --CI/DDIP): 517((M+NH₄ --H₂ O)⁺, 7%);499((M+H--H₂ O)⁺, 100%).

Example 15FS and 15FT

A flask was charged with lithium chloride (1.02 g, 24.0 mmol, 1.2equiv.) and flame dried in vacuo. A nitrogen atmosphere was introducedand dry dimethylformamide (12.0 ml) was added. The flask was cooled to0° C. and the starting alcohol, 2-furylmethanol (1.7 ml, 20.0 mmol) wasadded via syringe. The reagents, 2,6-lutidine (3.5 ml, 30.0 mmol, 1.5equiv., distilled from calcium hydride) and methanesulfonyl chloride(1.7 ml, 22.0 mmol, 1.1 equiv.), were added and stirring continued forone hour. The reaction was poured onto ice and extracted with ether. Theethereal layer was washed with a saturated aqueous solution of sodiumcarbonate, whereupon a precipitate formed. The precipitate was removedby filtration and the layers separated. The organic layer was dried withanhydrous sodium carbonate. The product was isolated by filtration andremoval of solvent on an ice cooled rotary evaporator. When the volumeneared 20 ml, the flask was removed from the rotary evaporator, flushedwith nitrogen and diluted with dry dimethylformamide (20.0 ml). Thissolution containing 2-chloromethylfuran was used withoutcharacterization in the next reaction.

The cyclic urea acetonide XXVIIIf (1.02 g, 2.79 mmol) was added to thesolution of 2-chloromethylfuran. Sodium hydride (490 mg, 16.3 mmol, 5.9equiv., 80% oil dispersion) was added and stirring continued for onehour. The reaction was then quenched by the addition of water andextracted with ethyl acetate-hexanes (1:1). The organic phase was washedtwice with water, once with brine, and dried over anhydrous magnesiumsulfate. Filtration and evaporation gave the crude product which waspurified by flash column chromatography (30% ethyl acetate-70% hexanes).The column provided two major fractions: a nonpolar fraction containingthe significantly contaminated bis-alkylated product and a polarfraction containing adequately pure mono-alkylated cyclic ureaintermediate (343 mg). ¹ H-NMR (300 MHz, CDCl₃) δ 7.28(11H, m), 6.27(1H,t), 6.05(1H, d), 5.07(1H, d), 4.83(1H, d), 4.22(1H, dd), 3.88(2H, m),3.48(1H, m), 3.15-2.88(4H, m), 2.70(1H, t), 1.48(3H, s), 1.46(3H, s).HRMS(NH₃ CI) Calculated for C₂₇ H₃₁ N₂ O₄ (M+H): 447.2284; observed:447.2277. The nonpolar fraction was further purified by flash columnchromatography (15% ethyl acetate-85% hexanes) to give purebis-alkylated intermediate (73.4 mg, 5%). ¹ H-NMR (300 MHz, CDCl₃) δ7.37-7.09(11H, m), 6.27(2H, dd), 6.08(2H, d), 4.94(2H, d), 3.90(2H, s),3.82(2H, b), 3.03(2H, d), 2.90(4H, m), 1.41(6H, s). ¹³ C NMR (75.4 MHz,CDCl₃) δ 160.74, 151.93, 142.19, 138.86, 129.45, 128.57, 126.46, 110.21,108.71, 75.26, 61.49, 48.45, 32.87, 26.71. MS(NH₃ CI) m/e 527 (M+H).

The monoalkylated cyclic urea acetonide above (33.5 mg, 0.075 mmol) wasdissolved in methanol (3.0 ml). p-Toluenesulfonic acid monohydrate (2.9mg) was added and stirring continued for four hours. The reaction wasquenched by the addition of saturated aqueous sodium carbonate. Thesolvent was removed on a rotary evaporator and the residue applied to aflash silica gel column. The column was eluted with initially 50% ethylacetate-50% hexanes and finally 100% ethyl acetate. This provided 15FS(27.8 mg, 91%) in excellent yield. ¹ H-NMR (300 MHz, CD₃ OD) δ 7.43(1H,s), 7.34-7.12(10H, m), 6.31(1H, m), 6.10(1H, d), 4.75(1H, d), 3.86(1H,dd), 3.65(2H, m), 3.39(1H, m), 3.11(2H, m), 3.01(1H, dd), 2.88(1H, d),2.77(1H, dd). ¹³ C NMR (75.4 MHz, CD₃ OD) δ 162.17, 151.45, 142.30,139.79, 139.74, 129.10, 129.06, 128.08, 127.91, 125.96, 125.64, 109.80,108.15, 70.90, 70.53, 65.28, 58.73, 32.70, 31.94. HRMS(NH₃ CI)Calculated for C₂₄ H₂₇ N₂ O₄ (M+H): 407.1971; Observed: 407.1961.

The bisalkylated acetonide was deprotected using the same procedure.Flash silica gel chromatography using 50% ethyl acetate-50% hexanes gave15FT in 83% yield. ¹ H-NMR (400 MHz, CD₃ OD) δ 7.44(2H, dd),7.32-7.13(10H, m), 6.33(2H, dd), 6.15(2H, d), 4.75(2H, d), 3.64(2H, bd),3.60(2H, s), 3.05-2.89(6H, m). ¹³ C NMR (100.6 MHz, CD₃ OD) δ 163.11,153.01, 143.93, 130.63, 129.47, 127.38, 111.36, 110.01, 71.75, 67.24,48.88, 32.99. HRMS(NH₃ CI): Calculated for C₂₉ H₃₁ N₂ O₅ (M+H):487.2233; Observed: 487.2226.

Example 15FU

The starting 3-carbomethoxy-2,5-dihydrothiophene was prepared from1,4-dithiane-2,5-diol, trimethylphosphonoacrylate and triethylamine asdescribed in the literature J. Org. Chem. 43 (23) 4431 (1978)!. Theresulting ester (1.03 g, 7.15 mmol) was dissolved in dry methylenechloride (16.0 ml) and cooled to -78° C. under a nitrogen atmosphere. Asolution of diisobutylaluminum hydride (11.9 ml, 17.88 mmol, 2.5 equiv.,1.5M in toluene) was added and stirring continued for two hours. Thereaction was then briefly warmed to room temperature then recooled to-78° C. Excess reagent was then quenched with methanol (5.0 ml) and thereaction was allowed to warm to room temperature. The reaction wasdiluted with ether and treated with a saturated solution of sodiumpotassium tartrate. The clarified aqueous phase was extracted with twoadditional portions of ether. The combined organic layers were driedwith magnesium sulfate, filtered and evaporated. Purification wasaccomplished by flash silica gel chromatography (5% methanol 95%methylene chloride). The resulting 3-hydroxymethyl-2,5-dihydrothiophenewas isolated in 91% yield (753.7 mg). ¹ H-NMR (300 MHz, CDCl₃) δ5.77(1H, bs), 4.22(2H, d), 3.74(4H, m), 2.09(1H, t). ¹³ C NMR (75.4 MHz,CDCl₃) δ 142.77, 124.13, 61.39, 38.45, 38.21. MS(CH₄ CI) m/e 117 (M+H).

Ths alcohol (663.0 mg, 5.72 mmol) was dissolved in dry methylenechloride (20 ml) under a nitrogen atmosphere. Dry triethylamine (1.2 ml,8.57 mmol, 1.5 equiv.) was added and the reaction cooled to 0° C.Methanesulfonic anhydride (1.2 g, 6.86 mmol, 1.2 equiv.) was added andreaction continued for 0.5 hours. The reaction was diluted withmethylene chloride and washed with dilute hydrochloric acid and brine.Drying over magnesium sulfate, filtration and evaporation gave the crudemesylate which was used without purification.

The residue was dissolved in dry dimethylformamide (5.0 ml) and thecyclic urea acetonide XXVIIIf (524.5 mg, 1.43 mmol) was added. Sodiumhydride (172 mg, 5.72 mmol, circa 4 equiv., 80% oil dispersion) wasadded and stirring continued overnight. The reaction was quenched by thecareful addition of water and extracted with 50% ethyl acetate-50%hexanes. The organic phase was washed twice with water, once with brine,and dried over magnesium sulfate. Filtration and evaporation gave thecrude product which was purified by flash silica gel chromatography (15%ethyl acetate-85% hexanes). The desired bisalkylated product wasobtained in excellent yield (720.1 mg, 90%). ¹ H-NMR (300 MHz, CDCl₃) δ7.29(6H, m), 7.14(4H, d), 5.40(2H, s), 4.32(2H, d), 4.08(2H, s),3.83(2H, d), 3.78-3.49(8H, m), 3.06(2H, dd), 2.87(2H, d), 2.83(2H, dd),1.31(6H, s). HRMS(NH₃ CI) Calculated for C₃₂ H₃₉ N₂ O₃ S₂ (M+H)⁺ :563.2402; Observed: 563.2394.

Removal of the acetonide protecting group using the hydrolysis proceduredescribed in the procedure of example 15FS gave compound 15FU. (34.1 mg,78%). ¹ H-NMR (300 MHz, CDCl₃) δ 7.36-7.11(10H, m), 5.45(2H, bs),4.27(2H, d), 3.93(2H, bs), 3.82-3.49(10H, m), 3.16(2H, dd), 2.87(2H,dd), 2.84(2H, d), 2.62(2H, bs). ¹³ C-NMR (75.43 MHz, CDCl₃) δ 162.14,139.66, 139.10, 129.36, 128.66, 128.51, 126.70, 71.81, 63.01, 50.97,39.70, 38.31, 32.91. HRMS(NH₃ CI) Calculated for C₂₉ H₃₅ N₂ O₃ S₂ (M+H):523.2089; Observed: 523.2071.

Example FW

Compound 15FU, protected as the acetonide, (53.2 mg, 0.0947 mmol) wasdissolved in dry methylene chloride (2.0 ml) under a nitrogenatmosphere. The reaction was cooled to 0° C. and solidm-chloroperoxybenzoic acid (83.7 mg, 0.388 mmol, 4.1 equiv., circa 80%active) was added and stirring continued for three hours with gradualwarming to room temperature. The reaction was then diluted withmethylene chloride and washed successively with saturated sodiumbisulfite, saturated sodium carbonate, and brine. The organic phase wasdried with magnesium sulfate, filtered and evaporated. The crude productwas purified by flash silica gel chromatography (50% ethyl acetate-50%hexanes) to give the bis-sulfone acetonide (61.5 mg, slightly more thantheoretical). This material was of sufficient purity for the subsequenttransformations. ¹ H-NMR (300 MHz, CDCl₃) δ 7.39-6.95(10H, m), 5.60(2H,bs), 4.22(2H, d), 4.06(2H, s), 3.83-3.47(10H, m), 3.13(2H, d), 2.99(2H,d), 2.73(2H, dd), 1.31(6H, s). MS(NH₃ CI) m/e 563(M+H--SO₂),499(M+H--2SO₂).

Removal of the acetonide protecting group using the hydrolysis proceduredescribed in the procedure of example 15FS gave compound 15FV (17.4 mg,65%). ¹ H-NMR (300 MHz, CDCl₃) δ 7.28(6H, m), 7.11(4H, d), 5.57(2H, bs),4.16(2H, d), 3.92(2H, s), 3.83-3.45(10H, m), 3.23(2H, d), 2.92(2H, d),2.74(2H, t). ¹³ C-NMR (100.6 MHz, CDCl₃) δ 161.99, 139.00, 135.52,129.32, 128.84, 127.04, 123.28, 71.04, 63.84, 56.53, 53.07, 33.14.HRMS(FAB (glycerol/TFA)): Calculated for C₂₉ H₃₅ N₂ O₇ S₂ (M+H):587.1886; Observed: 587.1889.

Example 15FW

Compound 15FU, protected as the acetonide, (46.6 mg, 0.0829 mmol) wasdissolved in dry 1,2-dichloroethane (2.0 ml). Addition of2,3-dichloro-5,6-dicyanobenzoquinone (41.4 mg, 0.182 mmol, 2.2 equiv.)resulted in an instantaneous conversion to product. The reaction wasapplied to a flash silica gel column and eluted with first methylenechloride then 5% methanol-95% methylene chloride. The desiredbis-thiophene intermediate was isolated in 92% yield (42.4 mg). ¹ H-NMR(300 MHz, CDCl₃) δ 7.37-7.20(8H, m), 7.10(4H, d), 6.98(2H, d), 6.95(2H,b), 4.88(2H, d), 3.83(2H, bs), 3.80(2H, bd(obscured)), 3.16(2H, d),2.92(2H, dd), 2.82(2H, dd), 1.37(6H, s). ¹³ C-NMR (75.4 MHz, CDCl₃) δ161.29, 139.01, 138.84, 129.43, 128.71, 127.74, 126.53, 126.37, 123.87,110.19, 75.59, 60.89, 51.00, 33.58, 26.79.

MS(NH₃ CI) m/e 559 (M+H).

After deprotection of the acetonide as descirbed for example 15FS, theresulting residue was applied to a preparative silica gel plate (0.25mm) and eluted with 50% ethyl acetate-50% hexanes. Isolation of theappropriate fractions gave compound 15FW (12.9 mg, 61%). ¹ H-NMR (300MHz, CDCl₃) δ 7.38(8H, m), 7.12(4H, d), 7.00(2H, dd), 6.97(2H, bd),4.82(2H, d), 3.64(2H, s), 3.58(2H, bd), 3.16(2H, d), 3.04(2H, dd),2.89(2H, dd), 2.34(2H, bs). ¹³ C-NMR (75.4 MHz, CDCl₃) δ 161.69, 139.4,138.92, 129.46, 128.68, 127.98, 126.58, 126.43, 124.07, 71.77, 64.04,50.20, 32.81. MS(NH₃ CI) m/e 519(M+H).

Example 15FX

Compound 15FV, protected as the acetonide, (15.5 mg, 0.024 mmol) wasdissolved in dry toluene (5.0 ml) under nitrogen. The reaction washeated at reflux for seven hours then allow to cool overnight. Thesolvent was removed under reduced pressure and the residue applied to apreparative silica gel plate (0.25 mm) and eluted with 25% ethylacetate-75% hexanes. The bis-diene intermediate was isolated in 61%yield (7.5 mg). ¹ H-NMR (300 MHz, CDCl₃) δ 7.37-7.17(10H, m), 6.31(2H,dd), 5.35(2H, d), 5.14(2H, s), 5.13(2H, d), 4.83(2H, d), 4.70(2H, d),3.88(2H, s), 3.85(2H, m), 2.89(4H, m), 2.64(2H, d), 1.44(6H, s) ¹³ C-NMR(100.6 MHz, CDCl₃) δ 161.68, 142.93, 139.49, 136.85, 129.39, 128.64,126.49, 120.23, 115.46, 110.22, 75.76, 59.19, 52.81, 33.40, 26.90.MS(NH₃ CI) m/e 499(M+H).

After deprotection of the acetonide as described for example 15FS, theresulting residue was applied to a preparative silica gel plate (0.25mm) and eluted with 50% ethyl acetate-50% hexanes. Isolation of theappropriate fractions gave compound 15FX (2.9 mg, 42%). ¹ H-NMR (400MHz, CDCl₃) δ 7.37-7.16(10H, m), 6.31(2H, dd), 5.34(2H, d), 5.17(2H, s),5.12(2H, d), 4.79(2H, s), 4.74(2H, d), 3.76(2H, s), 3.64(2H, d),3.06-2.88(4H, m), 2.67(2H, d), 2.28(2H, s). ¹³ C-NMR (100.6 MHz, CDCl₃)δ 162.02, 143.05, 139.93, 136.88, 129.48, 128.68, 126.47, 120.08,115.61, 71.89, 63.06, 52.42, 32.68. HRMS(NH₃ CI): Calculated for C₂₉ H₃₅N₂ O₃ (M+H): 459.2648; Observed: 459.2653.

                                      TABLE 2d                                    __________________________________________________________________________     ##STR77##                                                                                                                          MS                      Ex. Stereo                               HPLC         M + H                   No. 2:3:4:5                                                                           R.sup.22        R.sup.23         K.sub.1                                                                           IC.sub.90                                                                         mp, °C.                                                                     (M                                                                                  Notessub.4)       __________________________________________________________________________    9A  RSSR                                                                              m-(HO           m-(HONHCH.sub.2) ++  +++ 214- 595                             NCH)C.sub.6 H.sub.4 CH.sub.2                                                                  C.sub.6 H.sub.4 CH.sub.2                                                                       +       216                          9B  RSSR                                                                              m-(HONHCH.sub.2)                                                                              m-(HONHCH.sub.2) ++  +++                                      C.sub.6 H.sub.4 CH.sub.2 .HOAc                                                                C.sub.6 H.sub.4 CH.sub.2 .HOAc                                                                 +                                    9C  RSSR                                                                              m-(HONHCH.sub.2)                                                                              m-(HONHCH.sub.2) ++  +++      610                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                                                                       +                                    9D  RSSR                                                                              m-(C.sub.6 H.sub.5 CH.sub.2 ONCH)                                                             m-(C.sub.6 H.sub.5 CH.sub.2 ONCH)                                                              ++  ++  170.5-                                                                             790                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2 171                          9E  RSSR                                                                              m-(HONHCH.sub.2)                                                                              m-(HONHCH.sub.2) ++  +++                                      C.sub.6 H.sub.4 CH.sub.2 .HCl                                                                 C.sub.6 H.sub.4 CH.sub.2 .HCl                                                                  +                                    9F  RSSR                                                                              m-(C.sub.6 H.sub.5 CH.sub.2 ONHCH.sub.2)                                                      m-(C.sub.6 H.sub.5 CH.sub.2 ONHCH.sub.2)                                                       ++  +        775                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2      (792)                   9G  RSSR                                                                              m-(CH.sub.3 OC(O)O)                                                                           m-(CH.sub.3 OC(O)O)                                                                            ++  +++ 146- 655                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                                                                       +       147                          9H  RSSR                                                                              m-(CH.sub.3 CH(OH))                                                                           m-(CH.sub.3 CH(OH))                                                                            ++  +++      612                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                                                                       +                                    9I  RSSR                                                                              m-(CH.sub.3 NHCH.sub.2)                                                                       m-(CH.sub.3 NHCH.sub.2)       593                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              9J  RSSR                                                                              m-(HOCH.sub.2 CH.sub.2 NCH)                                                                   m-(HOCH.sub.2 CH.sub.2 NCH)                                                                    ++  +++      649                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                                                                       +                                    9K  RSSR                                                                              m-(HOCH.sub.2 CH.sub.2 NCH) C.sub.6 H.sub.4l CH.sub.2                                          ##STR78##       ++ +                                                                              +++      649                     9L  RSSR                                                                              m-(C.sub.6 H.sub.5 CH.sub.2 NHC(O)                                                            m-(C.sub.6 H.sub.5 CH.sub.2 NHC(O)                                                             ++  +++ 150  805                             O)-C.sub.6 H.sub.4 CH.sub.2                                                                   O)-C.sub.6 H.sub.4 CH.sub.2                                                                    +       (dec)                        9M  RSSR                                                                              m-(CH.sub.3 NHC(O))O)                                                                         m-(CH.sub.3 NHC(O))O)                                                                          ++  +++ 150  670                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                                                                       +       (dec)                        9N  RSSR                                                                              m-(HOCH.sub.2 CC)                                                                             m-BrC.sub.6 H.sub.4 CH.sub.2                                                                   ++  +++      639/641                         C.sub.6 H.sub.4 CH.sub.2         +            (656/658)               9o  RSSR                                                                              m-(CH.sub.3 C(O))                                                                             m-BrC.sub.6 H.sub.4 CH.sub.2                                                                   ++  +++ 190- 644/646                         C.sub.6 H.sub.4 CH.sub.2         +       191                          9P  RSSR                                                                              m-(CH.sub.3 C(O))                                                                             m-(CH.sub.3 C(O))                                                                              ++  +++ 158- 608                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                                                                       +       159                          9Q  RSSR                                                                              m-(CH.sub.3 C(NOH))                                                                           m-(CH.sub.3 C(NOH))                                                                            ++  +++ 200- 621                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                                                                       +       202                          9R  RSSR                                                                              m-(CH.sub.3 CH(OH))                                                                           m-BrC.sub.6 H.sub.4 CH.sub.2                                                                   ++  +++      629/631                         C.sub.6 H.sub.4 CH.sub.2         +                                    9S  RSSR                                                                              m-(ClCH.sub.2)-C.sub.6 H.sub.4 CH.sub.2                                                       m-(ClCH.sub.2)-C.sub.6 H.sub.4 CH.sub.2                                                        ++  +++ 156- 603                                                              +       157                          9T  RSSR                                                                              m-(5-tetrazolyl)                                                                              m-(5-tetrazolyl) +++ +   159.4                                                                              643.2893                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              9U  RSSR                                                                              m-(5-tetrazolyl)                                                                              cyclopropyl-methyl                                                                             +++ +++ 171.6                                                                              539.2771                        C.sub.6 H.sub.4 CH.sub.2                                              10A RSSR                                                                              m-(CO.sub.2 H)  H                +++ +   141˜143                                                                            2                         C.sub.6 H.sub.4 CH.sub.2                                              10C RSSR                                                                              m-(NC)          m-(OHC)C.sub.6 H.sub.4 CH.sub.2                                                                +++ +++ 189-191                                                                            560   4                         C.sub.6 H.sub.4 CH.sub.2                      (577)                   10D RSSR                                                                              m-(CH.sub.3 ONCH)                                                                             m-(CH.sub.3 ONCH)                                                                              ++  +   183˜185                                                                      (638) 5                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              10E RSSR                                                                              p-(CH.sub.3 C(O)O)                                                                            p-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                 +++ +++ 110˜112                                                                      623   6                         C.sub.6 H.sub.4 CH.sub.2                                              10F RSSR                                                                              m-(CH.sub.3 C(O)O)                                                                            m-(CH.sub.3 C(O)O)                                                                             ++  +++      623   8                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              10G RSSR                                                                              m-(NH.sub.2 C(O))                                                                             m-(NH.sub.2 C(O))                                                                              +++ +++      (610) 7                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              10H RSSR                                                                              m-(NH.sub.2 C(O)                                                                              m-(NH.sub.2 C(O) +++ +++      NMR only                        CH.sub.2 O)C.sub.6 H.sub.4 CH.sub.2                                                           CH.sub.2 O)C.sub.6 H.sub.4 CH.sub.2                   10I RSSR                                                                              m-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                H                +++ +++ 193˜194                                                                      433   2                 10J RSSR                                                                              m-(CH.sub.3)C.sub.6 H.sub.4 CH.sub.2                                                          m-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                 +++ +++      537   3                 10K RSSR                                                                              2-Naphthylmethyl                                                                              m-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                 +++ +++ 137˜138                                                                      573   3                 10L RSSR                                                                              p-(CH.sub.3 C(O)O)                                                                            p-(CH.sub.3 C(O)O)                                                                             ++  +++      623   8                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              10M RSSR                                                                              m-(NH.sub.2 NHC(O))                                                                           m-(NH.sub.2 NHC(O))                                                                            +++ +++ 205  623   7                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              10N RSSR                                                                              p-(NH.sub.2 NHC(O))                                                                           p-(NH.sub.2 NHC(O))                                                                            +++ +++ 215˜217                                                                      623   7                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              10o RSSR                                                                              p-(HOCH.sub.2)  m-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                 +++ +++ 141˜144                                                                      553   3                         C.sub.6 H.sub.4 CH.sub.2                                              10P RSSR                                                                              m-(NH.sub.2 C(O)NHNCH)                                                                        m-(NH.sub.2 C(O)NHNCH)                                                                         +++ +++ 301˜303                                                                            5                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              10Q RSSR                                                                              2-picolinyl-    m-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                 ++  +++      524   3                 10R RSSR                                                                              m-(CH.sub.3 ONHC(O))                                                                          m-(CH.sub.3 ONHC(O))                                                                           +++ +++ 150˜158                                                                      (670) 7                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              10S RSSR                                                                              p-(CH.sub.3 ONHC(O))                                                                          p-(CH.sub.3 ONHC(O))                                                                           +++ +++ 186˜189                                                                      653   7                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              10T RSSR                                                                              m-(HOCH.sub.2 CH(OH)                                                                          m-(HOCH.sub.2 CH(OH)                                                                           +++ +++ 113˜115                                                                            9                         CH.sub.2 O)C.sub.6 H.sub.4 CH.sub.2                                                           CH.sub.2 O)C.sub.6 H.sub.4 CH.sub.2                   10U RSSR                                                                              m-(adamantamido)-                                                                             m-(adamantamido)-                                                                              +   +++ 183˜184                                                                      893   8                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              10V RSSR                                                                              m-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                m-(adamantamido)-                                                                              ++  +++ 196˜198                                                                      716   6                                         C.sub.6 H.sub.4 CH.sub.2                              10W RSSR                                                                              m-(CH.sub.3 CH.sub.2 OC(O))                                                                   m-(CH.sub.3 CH.sub.2 OC(O))                                                                    +++ +   178˜180                                                                      651   10                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              10X RSSR                                                                              m-(HONHC(O))    m-(HONHC(O))     +++ +   139˜143                                                                            11                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              10Y RSSR                                                                              m-(HOCH.sub.2 CH.sub.2 O)                                                                     m-(HOCH.sub.2 CH.sub.2 O)                                                                      +++ +++ 245˜247                                                                      627   12                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              10Z SRRS                                                                              p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +   ++  198˜199                                                                      567   1                 11A RSSR                                                                              m-(NH.sub.2 C(NH))                                                                            m-(NH.sub.2 C(NH))                                                                             ++  +   224˜226                                                                      591   13                        C.sub.6 H.sub.4 CH.sub.2 HOAc                                                                 C.sub.6 H.sub.4 CH.sub.2 HOAc                         11B RSSR                                                                              (HOCH.sub.2 CH(OH))                                                                           (HOCH.sub.2 CH(OH))                                                                            +++ +++ 135˜137                                                                      627   9                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                                      m, p, positions m, p, positions                                               mixture         mixture                                               11C RSSR                                                                              m-(NH.sub.2 C(O))                                                                             m-(NH.sub.2 C(NH))                                                                             +++ +++ 229˜231                                                                            4                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2 HOAC                         11D RSSR                                                                              p-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                p-(HO)-m-(HOCH.sub.2)                                                                          +++ ++  178˜180                                                                            14                                        C.sub.6 H.sub.3 CH.sub.2                              11E RSSR                                                                              p-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                p-(HO)-m-(OHC)   +++ +++      567   14                                        C.sub.6 H.sub.3 CH.sub.2                              11F RSSR                                                                              p-(CH.sub.3 CH.sub.2 OC(O))                                                                   p-(CH.sub.3 CH.sub.2 OC(O))                                                                    ++  +   174˜178                                                                      651   10                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              11G RSSR                                                                              m-(CH.sub.3 OC(O))                                                                            m-(CH.sub.3 NHC(O))                                                                            +++ +++ 158˜161                                                                      622   4                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2      (639)                   11H RSSR                                                                              m-(CH.sub.3 NHC(O))                                                                           m-(CH.sub.3 NHC(O))                                                                            +++ +++ 160˜163                                                                      621   7                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              11I RSSR                                                                              benzyl          m-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                 +++ +++ 189˜193                                                                      523   3                 11J RSSR                                                                              2-Naphthylmethyl                                                                              p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +++ +++ 199˜201                                                                      587   3                 11K RSSR                                                                              m-(HOCH.sub.2 CH(OH))                                                                         m-(HOCH.sub.2 CH(OH))                                                                          +++ +++      627   9                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              11L RSSR                                                                              p-(HOCH.sub.2 CH(OH))                                                                         p-(HOCH.sub.2 CH(OH))                                                                          +++ +++      627   9                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              11M RSSR                                                                              m-(HOCH.sub.2)  m-(CH.sub.3 NHC(O))                                                                            +++ +++ 107˜109                                                                      (611) 4                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2      594                     11N RSSR                                                                              p-(HOCH.sub.2)  H                +++ +++ 112˜114                                                                      447   2                         C.sub.6 H.sub.4 CH.sub.2                                              11o RSSR                                                                              m-((HO).sub.2 B)                                                                              m-((HO).sub.2 B) +++ +++ 263˜267                                                                            15                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              11P RSSR                                                                              m-(NO.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                          m-(C.sub.6 H.sub.5 CH.sub.2 O)C.sub.6 H.sub.4                                 CH.sub.2         +++ +++ 173˜176                                                                      (675) 3                 11Q RSSR                                                                              m-(NH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                          m-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                 +++ +++ 116˜120                                                                      538   3                 11R RSSR                                                                              m-(CH.sub.3 CH.sub.2 NHC                                                                      m-(CH.sub.3 CH.sub.2 NHC(O))                                                                   +++ +++ 135˜138                                                                      649   7                         (O))C.sub.6 H.sub.4 CH.sub.2                                                                  C.sub.6 H.sub.4 CH.sub.2                              11S RSSR                                                                              m-((CH.sub.3).sub.2 N                                                                         m-((CH.sub.3).sub.2 NC(O))                                                                     ++  +++ 132˜134                                                                      649   7                         C (O))C.sub.6 H.sub.4 CH.sub.2                                                                C.sub.6 H.sub.4 CH.sub.2                              11T RSSR                                                                              m-(CH.sub.3 O.sub.2 C)C.sub.6 H.sub.4 CH.sub.2                                                m-((CH.sub.3 CH.sub.2).sub.2 NC                                               (O))C.sub.6 H.sub.4 CH.sub.2                                                                   +++ +++      (681) 4                 11U RSSR                                                                              m-(CH.sub.3 O.sub.2 C)                                                                        m-(CH.sub.3 CH.sub.2 NHC                                                                       +++ +++      (653) 4                         C.sub.6 H.sub.4 CH.sub.2                                                                      (O))C.sub.6 H.sub.4 CH.sub.2                          12A RSSR                                                                              6-amino-1-hexyl 6-amino-1-hexyl  +   +        525                     12B RSSR                                                                              6-amino-1-hexyl benzyl           ++  +        516                     12C RSSR                                                                              6-hydroxy-1-hexyl                                                                             H                +++ +++      427                     12D RSSR                                                                              6-hydroxy-1-hexyl                                                                             6-hydroxy-1-hexyl                                                                              +++ +++      527                     12E RSSR                                                                              cyclopropyl methyl                                                                            6-hydroxy-1-hexyl                                                                              +++ +++      481                     12F RSSR                                                                              4-hydroxy-1-butyl                                                                             4-hydroxy-1-butyl                                                                              ++  ++       471                     12G RSSR                                                                              5-carboxy-1-pentyl                                                                            5-carboxy-1-pentyl                                                                             +++ +++      555                     12H RSSR                                                                              5-carbomethoxy-1-                                                                             5-carbomethoxy-1-                                                                              ++  ++       583                             pentyl          pentyl                                                12I RSSR                                                                              5-carbomethoxy-1-                                                                             5-carboxy-1-pentyl                                                                             +++ +                                        pentyl                                                                12J RSSR                                                                              3-iodobenzyl    3-iodobenzyl     +++ +++      759                     12K RSSR                                                                              8-hydroxy-1-octyl                                                                             8-hydroxy-1-octyl                                                                              ++  +++      583                     12L RSSR                                                                              2-(hydroxy      2-(hydroxy       ++           495                             methyl)-        methyl)-                                                      cyclopropyl-methyl                                                                            cyclopropyl-                                                                  methyl                                                12M RSSR                                                                              benzyl          2-(hydroxy       +++ +++      501                                             methyl)-                                                                      cyclopropyl-                                                                  methyl                                                12N RSSR                                                                              2-(hydroxy      H                ++  +        411                             methyl)-                                                                      cyclopropyl-                                                                  methyl                                                                12o RSSR                                                                              7-hydroxy-1-heptyl                                                                            H                ++  ++       411                     12P RSSR                                                                              7-hydroxy-1-heptyl                                                                            7-hydroxy-1-heptyl                                                                             ++  +++      555                     12Q RSSR                                                                              3-(carbamoyl    3-(carbamoyl     +++ +   185  655                             thio)benzyl     thio)benzyl                                           12R RSSR                                                                              (3-methylthio)  (3-methylthio)   +++ +++ 169  599                             benzyl          benzyl                                                12S RSSR                                                                              3-              3-               +++ +++      633                             (methylsulfonyl)benzyl                                                                        (methylsulfonyl)benzyl                                12T RSSR                                                                              2- (2-hydroxy   H                ++  +        415                             ethyl)oxy!ethyl                                                       12U RSSR                                                                              2- (2-hydroxy   2- (2-hydroxy    +   ++       503                             ethyl)oxy!ethyl ethyl)oxy!ethyl                                       12V RSSR                                                                              6-acetoxy-1-hexyl                                                                             6-hydroxy-1-hexyl                                                                              ++  +++      569                     12W RSSR                                                                              6-(N-methylamino                                                                              6-(N-methylamino ++  ++       641                             carboxy)-1-hexyl                                                                              carboxy)-1-hexyl                                      12X RSSR                                                                              6-(N-methylamino                                                                              6-acetoxy-1-hexyl                                                                              ++  +++      626                             carboxy)-1-hexyl                                                      12Y RSSR                                                                              6-(N-methylamino                                                                              6-acetoxy-1-hexyl                                                                              +++          584                             carboxy)-1-hexyl                                                      12Z RSSR                                                                              2-(2-hydroxy    H                ++           425   16                        ethyl)                                                                        cyclopropyl-                                                                  methyl                                                                13A RSSR                                                                              2-(3-           H                ++           439   16                        hydroxypropyl)-                                                               cyclopropyl-                                                                  methyl                                                                13B RSSR                                                                               2-(2-          H                ++           481   16                        hydroxypropyl)-                                                               3,3-dimethyl!                                                                 cyclopropyl methyl                                                    13C RSSR                                                                               2-(2-           2-(2-           +            635                             hydroxypropyl)- hydroxypropyl)-               (652)                           3,3-dimethyl!   3,3-dimethyl!                                                 cyclopropyl-    cyclopropyl-                                                  methyl          methyl                                                13D RSSR                                                                              6-hexenyl       6-hexenyl        +++ +++      491                     13E RSSR                                                                              5,6-epoxy-1-hexyl                                                                             5,6-epoxy-1-hexyl                                                                              ++  +++      523                     13F RSSR                                                                              5,6-dibromo-1-  5,6-dibromo-1-   ++  +        811                             hexyl           hexyl                                                 13G RSSR                                                                              6-bromo-5-hydroxy-                                                                            6-bromo-5-hydroxy-                                                                             +++ +++      685                             1-hexyl         1-hexyl                                               13H RSSR                                                                              5-hydroxy-1-pentyl                                                                            5-hydroxy-1-pentyl                                                                             +++ +++      499                     13I RSSR                                                                              5,6-dihydroxy-1-                                                                              5,6-dihydroxy-1- +++ +        559                             hexyl           hexyl                                                 13J RRSR                                                                              cyclopropyl-    cyclopropyl-     +++ +++      435                             methyl          methyl                                                13K RRSR                                                                              allyl           allyl            +++ +++      407                     13L RRSR                                                                              benzyl          benzyl           +++ +++      507                     13M RRSR                                                                              4-(hydroxy      4-(hydroxy       +++ +++      567                             methyl)benzyl   methyl)benzyl                                         13N RRRR                                                                              allyl           allyl            +   ++       407                     13o RRRR                                                                              cyclopropyl-methyl                                                                            cyclopropyl-methyl                                                                             +   ++       435                     13P RRRR                                                                              H               H                +   +        327                     13Q RRRR                                                                              benzyl          benzyl           +   +++      507                     13R RRRR                                                                              n-butyl         n-butyl          ++  +++      439                     13S RRRR                                                                              4-(hydroxy      4-(hydroxy       ++  ++       567                             methyl)benzyl   methyl)benzyl                                         13T RSSR                                                                              (1,2,3,4-       (1,2,3,4-        ++  +        617                             tetrahydro)-6-  tetrahydro)-6-                                                isoquinolyl-methyl                                                                            isoquinolyl-methyl                                    13U RSSR                                                                              6-isoquinolyl-  6-isoquinolyl-   ++  +   264-6                                                                              609                             methyl          methyl                                                13V RSSR                                                                              2-thiazolyl-methyl                                                                            2-thiazolyl-methyl                                                                             ++  ++       521                     13W RSSR                                                                              (5-t-           (5-t-            +   +++ 182-4                                                                              687                             butoxycarbonyl)-2-                                                                            butoxycarbonyl)-2-                                            furanylmethyl   furanylmethyl                                         13X RSSR                                                                              (5-hydroxymethyl)-                                                                            (5-hydroxymethyl)-                                                                             ++  +        547                             2-furanylmethyl 2-furanylmethyl                                       13Y RRRS                                                                              benzyl          benzyl           +   +++      507                     13Z RSSR                                                                              4-chloro-3-     4-chloro-3-      ++  +++      577                             pyridylmethyl   pyridylmethyl                 (594)                   14A RSSR                                                                              2-chloro-3-     2-chloro-3-      ++  ++                                       pyridylmethyl   pyridylmethyl                                         14B RSSR                                                                              2-(t-butylthio)-3-                                                                            2-(t-butylthio)-3-                                                                             ++  +++      685                             pyridylmethyl   pyridylmethyl                                         14C RSSR                                                                              4-hydroxy-3-    4-hydroxy-3-     ++  +        541                             pyridylmethyl   pyridylmethyl                                         14D RSSR                                                                              cyclopropyl-methyl                                                                            2-pyridyl        ++  +++      458                     14E RSSR                                                                              oct-2-yn-1-yl   oct-2-yn-1-yl    ++           543                     14F RSSR                                                                              3,3-diphenyl-2(R)-                                                                            3,3-diphenyl-2(R)-                                                                             ++           739   16                        cylopropylmethyl                                                                              cylopropylmethyl                                      14G RSSR                                                                              phenyl          phenyl           ++           479                     14H RSSR                                                                              3(S)-phenyl-2(R)-                                                                             3(S)-phenyl-2(R)-                                                                              ++           587   16                        cyclopropyl-methyl                                                                            cyclopropyl-methyl                                    14I RSSR                                                                              3(S)-phenyl-2(R)-                                                                             H                ++           457   16                        cyclopropyl-methyl                                                    14J RSSR                                                                              3-benzyloxy-5-  3-benzyloxy-5-   ++                                           methyl-4-       methyl-4-                                                     pyridylmethyl   pyridylmethyl                                         14K RSSR                                                                              3-hydroxy-5-    3-hydroxy-5-     ++  +                                        methyl-4-       methyl-4-                                                     pyridylmethyl   pyridylmethyl                                         15A RSSR                                                                              m-(H.sub.2 N)C.sub.6 H.sub.4 CH.sub.2                                                         p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +++ +++      552.29                                                                              17                15B RSSR                                                                              m-(CF.sub.3 O.sub.2 SNH)                                                                      m-(CF.sub.3 O.sub.2 SNH)                                                                       +++ ++  141.8                                                                              801.19                                                                              18                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15C RSSR                                                                              m-(H.sub.2 NCONH)                                                                             m-(H.sub.2 NCONH)                                                                              +++ +++            19                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15D RSSR                                                                              m-(CH.sub.3 NH)C.sub.6 H.sub.4 CH.sub.2                                                       m-(CH.sub.3 NH)C.sub.6 H.sub.4 CH.sub.2                                                        +++ +++ 180.3                                                                              565.32                                                                              20                15E RSSR                                                                              m-(C.sub.6 H.sub.5 CH.sub.2 OCONH)                                                            m-(C.sub.6 H.sub.5 CH.sub.2 OCONH)                                                             ++  +   190.7                                                                              822.39                                                                              21                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15F RSSR                                                                              m-(CH.sub.3 (OHC)N)                                                                           m-(CH.sub.3 (OHC)N)                                                                            ++  +++ 82.0 621.31                                                                              22                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15G RSSR                                                                              cyclopropyl-methyl                                                                            m-(H.sub.2 N)C.sub.6 H.sub.4 CH.sub.2                                                          +++ +++ 108.9                                                                              486.27                                                                              23                                        HCl                                                   15H RSSR                                                                              cyclopropyl-methyl                                                                            m-(O.sub.2 N)C.sub.6 H.sub.4 CH.sub.2                                                          +++ +++      516.25                  15I RSSR                                                                              m-((CH.sub.3).sub.2 N)                                                                        m-((CH.sub.3).sub.2 N)                                                                         +++ +++ 199.9                                                                              593.35                                                                              24                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15J RSSR                                                                              m-(O.sub.2 N)C.sub.6 H.sub.4 CH.sub.2                                                         p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +++ +++ 92.0 (599)                   15K RSSR                                                                              m-(H.sub.2 N)C.sub.6 H.sub.4 CH.sub.2                                                         m-(CH.sub.3 NHCONH)                                                                            +++     153.3                                                                              594.5 25                                        C.sub.6 H.sub.4 CH.sub.2                              15L RSSR                                                                              m-(CH.sub.3 NHCONH)                                                                           m-(CH.sub.3 NHCONH)                                                                            +++     173.7                                                                              (651.4)                                                                             25                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15M RSSR                                                                              m-(NHCH.sub.3)C.sub.6 H.sub.4 CH.sub.2                                                        p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +++ +++ 107.6                                                                              566.30                                                                              26                        . . . HCl                                                             15N RSSR                                                                              m-((CH.sub.3).sub.2 NCH.sub.2                                                                 m-((CH.sub.3).sub.2 NCH.sub.2                                                                  +++ +++ 92.8 707.39                                                                              27                        C(O)NH)C.sub.6 H.sub.4 CH.sub.2                                                               C(O)NH)C.sub.6 H.sub.4 CH.sub.2                               . . . HCl       . . . HCl                                             15Q RSSR                                                                              m-(CH.sub.3 NHCH.sub.2                                                                        m-(CH.sub.3 NHCH.sub.2                                                                         +++ +++ 202.6                                                                              679.36                                                                              27                        C(O)NH)C.sub.6 H.sub.4 CH.sub.2                                                               C(O)NH)C.sub.6 H.sub.4 CH.sub.2                               . . . HCl       . . . HCl                                             15P RSSR                                                                              m-((CH.sub.3).sub.2 NCH.sub.2                                                                 p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +++ +++ 108.1                                                                              637.34                                                                              27                        C (O)NH)C.sub.6 H.sub.4 CH.sub.2                                              . . . HCl                                                             15Q RSSR                                                                              m-(C.sub.6 H.sub.5 CH.sub.2 O                                                                 m-(C.sub.6 H.sub.5 CH.sub.2 O                                                                  +++ +++ 114.6      27                        C(O)NHCH.sub.2 C(O)NH)                                                                        C(O)NHCH.sub.2 C(O)NH)                                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15R RSSR                                                                              m-(H.sub.2 NCH.sub.2 C(O)NH)                                                                  m-(H.sub.2 NCH.sub.2 C(O)NH)                                                                   +++ +++ 233.7                                                                              651.33                                                                              27                        C.sub.6 H.sub.4 CH.sub.2 . .HCl                                                               C.sub.6 H.sub.4 CH.sub.2 . .HCl                       15S RSSR                                                                              m-(L            m-(L             +++     100.6                                                                              947.43                                                                              27                        C.sub.6 H.sub.5 CH.sub.2 OC(O)NH                                                              C.sub.6 H.sub.5 CH.sub.2 OC(O)NH                              CH(CH.sub.3)C(O)NH)                                                                           CH(CH.sub.3)C(O)NH)                                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15T RSSR                                                                              m-(LC.sub.6 H.sub.5 CH.sub.2 O                                                                m-(LC.sub.6 H.sub.5 CH.sub.2 O                                                                 +++     107.9                                                                              1099.50                                                                             27                        C(O)NHCH(CH.sub.2 C.sub.6 H.sub.5)C                                                           C(O)NHCH(CH.sub.2 C.sub.6 H.sub.5)C                           (O)NH)C.sub.6 H.sub.4 CH.sub.2                                                                (O)NH)C.sub.6 H.sub.4 CH.sub.2                        15U RSSR                                                                              m-(L            m-(L             +++     112.3                                                                              679.36                                                                              27                        H.sub.2 NCH(CH.sub.3)C(O)NH)                                                                  H.sub.2 NCH(CH.sub.3)C(O)NH)                                  C.sub.6 H.sub.4 CH.sub.2 . . . HCl                                                            C.sub.6 H.sub.4 CH.sub.2 . . . HCl                    15V RSSR                                                                              m-(L            m-(L             +++     210.6                                                                              831.42                                                                              27                        H.sub.2 NCH(CH.sub.2 C.sub.6 H.sub.5)                                                         H.sub.2 NCH(CH.sub.2 C.sub.6 H.sub.5)                         C(O)NH)C.sub.6 H.sub.4 CH.sub.2                                                               C(O)NH)C.sub.6 H.sub.4 CH.sub.2                               . . . HCl       . . . HCl                                             15VA                                                                              RSSR                                                                              H               4-oxocyclohexyl- ++  ++/+     437                                             methyl                                                15VB                                                                              RSSR                                                                              H               4,4-dimethoxy-   ++  ++/+     452                                             cyclohexylmethyl              (469)                   15VC                                                                              RSSR                                                                              H               4-(oxime)-       ++  ++/+     451                                             cyclohexylmethyl              (M + H                                                                        OCH.sub.3)              15VD                                                                              RSSR                                                                              CH.sub.3 NHC(O)(CH.sub.2).sub.5                                                               CH.sub.3 NHC(O)(CH.sub.2).sub.5                                                                ++  ++       581                             --              --                            (598)                   15VE                                                                              RSSR                                                                              HO(CH.sub.2).sub.6                                                                            Cl(CH.sub.2).sub.6                                                                             ++  +++      545   28                15VF                                                                              RSSR                                                                              HO(CH.sub.2).sub.6                                                                            CH.sub.3 NHSO.sub.3 (CH.sub.2).sub.6                                                           ++  +++      620   28                                                                      (637)                   15VG                                                                              RSSR                                                                              H               HO(CH.sub.2).sub.5                                                                             +++ +++      413   29                15VH                                                                              RSSR                                                                              HO(CH.sub.2).sub.5                                                                            b-Naphthyl-CH.sub.2                                                                            +++ +++ 84.6 553   28                15VI                                                                              RSSR                                                                              HO(CH.sub.2).sub.5                                                                            C.sub.6 H.sub.5 CH.sub.2                                                                       +++ +++      503   28                15VJ                                                                              RSSR                                                                              HO(CH.sub.2).sub.5                                                                            CH.sub.3 S(CH.sub.2).sub.5                                                                     ++  +++      529   28                15VK                                                                              RSSR                                                                              HO(CH.sub.2).sub.5                                                                            p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +++ +++      533                                             --                                                    15VL                                                                              RSSR                                                                              H               CH.sub.3 CH.sub.2 CH(OH)CH.sub.2                                                               ++  ++/+     399   30                15VM                                                                              RSSR                                                                              H               CH.sub.3 (CH.sub.2).sub.3 CH(OH)                                                               +   ++/+     427   31                                        CH.sub.2                                              15VN                                                                              RSSR                                                                              CH.sub.3 CH.sub.2 CH(OH)CH.sub.2                                                              CH.sub.3 CH.sub.2 CH(OH)CH.sub.2                                                               +   ++/+                                                                              99.2 471   30                15VO                                                                              RSSR                                                                              CH.sub.3 CH.sub.2 C(O)CH.sub.2                                                                CH.sub.3 CH.sub.2 C(O)CH.sub.2                                                                 ++  ++/+     467   32                15VP                                                                              RSSR                                                                              CH.sub.3 CH.sub.2 C(NOH)CH.sub.2                                                              CH.sub.3 CH.sub.2 C(NOH)CH.sub.2                                                               ++  ++       497   33                        --              --                                                    15VQ                                                                              RSSR                                                                              HO(CH.sub.2).sub.6                                                                            b-Naphthyl-CH.sub.2                                                                            +++ +++      567                     15VR                                                                              RSSR                                                                              HO(CH.sub.2).sub.5                                                                            m-HOC.sub.6 H.sub.4 CH.sub.2                                                                   +++ +++      519                     15VS                                                                              RSSR                                                                              HO(CH.sub.2).sub.5                                                                            CH.sub.3 SO.sub.2 (CH.sub.2).sub.5                                                             +++ +++      561                                                                           (578)                   15VT                                                                              RSSR                                                                              HO(CH.sub.2).sub.5                                                                            CH.sub.3 SO(CH.sub.2).sub.5                                                                    +++ +++      545                                                                           (562)                   15VU                                                                              RSSR                                                                              HO(CH.sub.2).sub.5                                                                            C.sub.3 H.sub.5 CH.sub.2                                                                       +++ +++      467                     15VV                                                                              RSSR                                                                              CH.sub.3 O(CH.sub.2).sub.5                                                                    CH.sub.3 O(CH.sub.2).sub.5                                                                     ++  ++       527   34                                                                      (544)                   15VW                                                                              RSSR                                                                              HO(CH.sub.2).sub.5                                                                            CH.sub.3 O(CH.sub.2).sub.5                                                                     +++ +++      513   35                15VX                                                                              RSSR                                                                              HO(CH.sub.2).sub.5                                                                            m-CNC.sub.6 H.sub.4 CH.sub.2                                                                   +++ +++      528                                                                           (545)                   15VY                                                                              RSSR                                                                              HO(CH.sub.2).sub.5                                                                            m-(C.sub.2 H.sub.5 OC(O))                                                                      +++ +++      575                                             C.sub.6 H.sub.4 CH.sub.2      (592)                   15VZ                                                                              RSSR                                                                              CH.sub.3 CH(OH)(CH.sub.2).sub.4                                                               CH.sub.3 CH(OH)(CH.sub.2).sub.4                                                                +++ +++      527   36                                                                      (544)                   15WA                                                                              RSSR                                                                              CH.sub.3 CH(OH)(CH.sub.2).sub.4                                                               b-Naphthyl-CH.sub.2                                                                            +++ +++ 80.7 567   36                                                                      (584)                   15WB                                                                              RSSR                                                                              CH.sub.3 C(O)(CH.sub.2).sub.4                                                                 CH.sub.3 C(O)(CH.sub.2).sub.4                                                                  ++  ++       523   32                15WC                                                                              RSSR                                                                              CH.sub.3 C(NOH)(CH.sub.2).sub.4                                                               CH.sub.3 C(NOH)(CH.sub.2).sub.4                                                                ++  +++      553                             --              --                                                    15WD                                                                              RSSR                                                                              H.sub.2 N(CH.sub.2).sub.6                                                                     p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         ++  +++      546   37                                        --                                                    15WE                                                                              RSSR                                                                              HO(CH.sub.2).sub.5                                                                            m-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +++ +++      533                                             --                            (550)                   15WF                                                                              RSSR                                                                              m-(Et.sub.2 NC(O))                                                                            m-(Et.sub.2 NC(O))                                                                             +++ +++ 89-  (722) 38                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2 91                           15WG                                                                              RSSR                                                                              m-(MeO.sub.2 C)C.sub.6 H.sub.4 CH.sub.2                                                       m-(Et.sub.2 NC(O))                                                                             +++ +++      (681) 39                                        C.sub.6 H.sub.4 CH.sub.2                              15WH                                                                              RSSR                                                                              m-(MeO.sub.2 C)C.sub.6 H.sub.4 CH.sub.2                                                       m-(EtNHC(O))     +++ +++      (653) 39                                        C.sub.6 H.sub.4 CH.sub.2                              15WI                                                                              RSSR                                                                              H               m-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +++ +++ 176- 447   40                                                                 177                          15WJ                                                                              RSSR                                                                              m-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        m-Et.sub.2 NC(O) +++ +++ 88.9-                                                                              636   39                                        C.sub.6 H.sub.4 CH.sub.2 90.0 (20%)                   15WK                                                                              RSSR                                                                              m-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        m-(EtNHC(O))     +++ +++      608   39                                        C.sub.6 H.sub.4 CH.sub.2                              15WL                                                                              RSSR                                                                              m-(.sup.i Pr.sub.2 NC(O))                                                                     m-(.sup.i Pr.sub.2 NC(O))                                                                      +   +   165- 678   39                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2 167                          15WM                                                                              RSSR                                                                              m-(PrNHC(O))    m-(PrNHC(O))     +++ +++      677   38                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15WN                                                                              RSSR                                                                              m-(HO.sub.2 C)C.sub.6 H.sub.4 CH.sub.2                                                        m-(.sup.i PrNHC(O))                                                                            +++ +++ 164- 636   39                                        C.sub.6 H.sub.4 CH.sub.2 167                          15WQ                                                                              RSSR                                                                              m-(HO.sub.2 C)C.sub.6 H.sub.4 CH.sub.2                                                        m-(PrNHC(O))     +++ +++ 151- 636   39                                        C.sub.6 H.sub.4 CH.sub.2 153  (32%)                   15WP                                                                              RSSR                                                                              m-(HO.sub.2 C)C.sub.6 H.sub.4 CH.sub.2                                                        Benzyl           +++ +++ 122- (568) 39                                                                 124                          15WQ                                                                              RSSR                                                                              m-(HO.sub.2 C)C.sub.6 H.sub.4 CH.sub.2                                                        Cyclopropyl-methyl                                                                             +++ +++ 135- (532) 39                                                                 137                          15WR                                                                              RSSR                                                                              p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        m-(HO.sub.2 C)C.sub.6 H.sub.4 CH.sub.2                                                         +++ +++ 130- (598) 39                                                                 132                          15WS                                                                              RSSR                                                                              m-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        3-picolinyl      +++ +++      538   39                15WT                                                                              RSSR                                                                              p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        m-(H.sub.2 NC(O))                                                                              +++ +++ 123- 580   39                                        C.sub.6 H.sub.4 CH.sub.2 124                          15WU                                                                              RSSR                                                                              m-(H.sub.2 N)C.sub.6 H.sub.4 CH.sub.2                                                         2-naphthylmethyl +++ +++      572   39                15WV                                                                              RSSR                                                                              Cyclopropyl-methyl                                                                            m-(H.sub.2 NC(O))                                                                              +++ +++ 128- 514   39                                        C.sub.6 H.sub.4 CH.sub.2 130                          15WW                                                                              RSSR                                                                              H               m-(H.sub.2 NC(O))                                                                              +++ +++ 114- 460   39                                        C.sub.6 H.sub.4 CH.sub.2 116                          15WX                                                                              RSSR                                                                              m-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        m-(EtHNC(O))     +++ +++ 88-  580   39                                        C.sub.6 H.sub.4 CH.sub.2 89                           15WY                                                                              RSSR                                                                              m-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        m-(MeNH)C.sub.6 H.sub.4 CH.sub.2                                                               +++ +++ 111- 552   39                                                                 113                          15WZ                                                                              RSSR                                                                              m-(MeNH)C.sub.6 H.sub.4 CH.sub.2                                                              2-Naphthylmethyl +++ +++ 98-  586   39                                                                 100                          15XA                                                                              RSSR                                                                              p-(HO.sub.2 C)C.sub.6 H.sub.4 CH.sub.2                                                        p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +++ ++       (598) 41                15XB                                                                              RSSR                                                                              p-(HC(O))C.sub.6 H.sub.4 CH.sub.2                                                             p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +++ +++      565   42                15XC                                                                              RSSR                                                                              m-(MeNHCH.sub.2)                                                                              m-(MeNHCH.sub.2) ++  +++      593.3483                        C.sub.6 H.sub.4 CH.sub.2 .HCl                                                                 C.sub.6 H.sub.4 CH.sub.2 .HCl                         15XD                                                                              RSSR                                                                              m-(CH.sub.3 CHOH)                                                                             m-(CH.sub.3 CHOH)                                                                              +++ +++      595.3177                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2      (612)                   15XE                                                                              RSSR                                                                              3-picolinyl     p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +++ +++      538.2693                15XF                                                                              RSSR                                                                              m-(Et.sub.2 NCH.sub.2)                                                                        m-(Et.sub.2 NCH.sub.2)                                                                         ++  +++      677.4444                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15XG                                                                              RSSR                                                                              m-(N-imidazol-  m-(N-imidazol-   +++ +++      667.3394                        methyl)C.sub.6 H.sub.4 CH.sub.2                                                               methyl)C.sub.6 H.sub.4 CH.sub.2                       15XH                                                                              RSSR                                                                              m-(.sup.t BuC(O))                                                                             m-(.sup.t BuC(O))                                                                              +++ +++      675.3805                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15XI                                                                              RSSR                                                                              m-(CF.sub.3 CHOH)                                                                             m-(CF.sub.3 CHOH)                                                                              +++ +++      703.2611                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15XJ                                                                              RSSR                                                                              m- 2-imidazolyl-                                                                              m- 2-imidazolyl- +++ +++      695.2977                        C(O)!C.sub.6 H.sub.4 CH.sub.2                                                                 C(O)!C.sub.6 H.sub.4 CH.sub.2                         15XK                                                                              RSSR                                                                              3-picolinyl.HCl p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +++ +++      (538)                   15XL                                                                              RSSR                                                                              m-(HOCH.sub.2 CC)                                                                             m-(HOCH.sub.2 CC)                                                                              +++ +++      615.2853                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2      (632)                   15XM                                                                              RSSR                                                                              m-(CF.sub.3 C(O))                                                                             m-(CF.sub.3 C(O))                                                                              +++ +++      699.2286                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15XN                                                                              RSSR                                                                              m-(CH.sub.3 CH.sub.2 C(O))                                                                    m-(CH.sub.3 CH.sub.2 C(O))                                                                     +++ +++      639.3181                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2      (636)                   15Xo                                                                              RSSR                                                                              m- 3-pyrazolyl)-                                                                              m- 3-pyrazolyl)- +++ +++      639.3100                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2      (656)                   15XP                                                                              RSSR                                                                              m- EtC(NOH)!    m- EtC(NOH)!     +++ +++      (649)                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15XQ                                                                              RSSR                                                                              m-(NH.sub.2 SO.sub.2)                                                                         m-(NH.sub.2 SO.sub.2)                                                                          +++ +++      665.2103                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2      (682)                   15XR                                                                              RSSR                                                                              m- CF.sub.3 C(N m- CF.sub.3 C(N  +++ +++      729.2500                        OH)!C.sub.6 H.sub.4 CH.sub.2                                                                  OH)!C.sub.6 H.sub.4 CH.sub.2                          15XS                                                                              RSSR                                                                              m- MeC(NOH)!    m- MeC(NOH)!     +++ +++      621.3070                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15XT                                                                              RSSR                                                                              m-(H.sub.2 NCH.sub.2 C(O)NH)                                                                  p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                         +++ +++      645.20                          C.sub.6 H.sub.4 CH.sub.2  . . . HCl                                   15XU                                                                              RSSR                                                                              m-(2-(4-        m-(2-(4-         +++ +++ 102-105                                                                            819.4435                        morpholino)ethylNH                                                                            morpholino)ethylNH                                            C(O))C.sub.6 H.sub.4 CH.sub.2                                                                 C(O))C.sub.6 H.sub.4 CH.sub.2                         15XV                                                                              RSSR                                                                              m-(2-(N,N-      m-(2-(N,N-       +++          735.4226                        dimethylamino)- dimethylamino)-                                               ethylNHC(O))    ethylNHC(O))                                                  C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15XW                                                                              RSSR                                                                              m-(2-(N,N-      m-(2-(N,N-       +++ +++ 100-103                                                                            735.422676                      dimethylamino)- dimethylamino)-                                               ethylNHC(O))    ethylNHC(O))                                                  C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15XX                                                                              RSSR                                                                              CH3             m-(2-(N,N-           ++  101-103                                              dimethylamino)-                                                               ethylNHC(O))                                                                  C.sub.6 H.sub.4 CH.sub.2                              15XY                                                                              RSSR                                                                              CH3             m-(2-(N,N-       ++  +/++                                                                              118-120                                                                            587.323422                                      dimethylamino)-                                                               ethylNHC(O))                                                                  C.sub.6 H.sub.4 CH.sub.2                              15XZ                                                                              RSSR                                                                              CH3             benzyl(3-        ++  +/++                                                                              134-136                                                                            571.327642                                      (pyrrolidino                                                                  ethyl)benzamido)methyl                                15YA                                                                              RSSR                                                                              cyclopropylmethyl                                                                             m-(2-(N,N-       +++ +++ 97-99                                                                              585.343057                                      dimethylamino)-                                                               ethylNHC(O))                                                                  C.sub.6 H.sub.4 CH.sub.2                              15YB                                                                              RSSR                                                                              cyclopropylmethyl                                                                             m-(2-(4-         +++ +++ 103-105                                                                            627.354642                                      morpholino)ethylNH                                                            C(O))C.sub.6 H.sub.4 CH.sub.2                         15YC                                                                              RSSR                                                                              cyclopropylmethyl                                                                             benzyl(3-        +++ +++ 110-112                                                                            611.359872                                      (pyrrolidino                                                                  ethyl)benzamido)methyl                                15YD                                                                              RSSR                                                                              cyclopropylmethyl                                                                             m-((3-pyridyl)-  +++     115-117                                                                            605.311364                                      methylNHC(O))                                                                 C.sub.6 H.sub.4 CH.sub.2                              15YE                                                                              RSSR                                                                              cyclopropylmethyl                                                                             m-((2-pyridyl)-                                                               methylNHC(O))                                                                 C.sub.6 H.sub.4 CH.sub.2                              15YF                                                                              RSSR                                                                              m-(p-toluyl     m-(p-toluyl      ++  +++ 169-171                              sulfonylhydra-  sulfonylhydra-                                                zone-)C.sub.6 H.sub.4 CH.sub.2                                                                zone)C.sub.6 H.sub.4 CH.sub.2                         15YG                                                                              RSSR                                                                              m-(N-morpholino m-(N-morpholino  ++  +++ 110-112                                                                            765                             ethoxy)C.sub.6 H.sub.4 CH.sub.2                                                               ethoxy)C.sub.6 H.sub.4 CH.sub.2                       15YH                                                                              RSSR                                                                              p-HOCH.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                         p-H.sub.2 NCH.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                   ++  ++  132-134                                                                            566                     15YI                                                                              RSSR                                                                              m-(CH.sub.3 NHOCO)                                                                            m-(CH.sub.3 NHOCO)                                                                             +++ +++ 223-224                              C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15YJ                                                                              RSSR                                                                              m-(1,2,4-oxadia-                                                                              m-(1,2,4-oxadia- +++     202 (dec)                            zolidinon-3-yl)-                                                                              zolidinon-3-yl)-                                              C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15YK                                                                              RSSR                                                                              m-(2-imidazole)-                                                                              m-(N-SEM-2-      ++  +++      769                             C.sub.6 H.sub.4 CH.sub.2                                                                      imidazole)-                                                                   C.sub.6 H.sub.4 CH.sub.2                              15YL                                                                              RSSR                                                                              m-(3-pyrazole)- m-(3-pyrazole)-  +++ +++ 208-210                                                                            639.4                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15YM                                                                              RSSR                                                                              m-(3-pyrazole)- m-(3-pyrazole)-  +++ +++ 195-197                              C.sub.6 H.sub.4 CH.sub.2 .HCl                                                                 C.sub.6 H.sub.4 CH.sub.2 .HCl                         15YN                                                                              RSSR                                                                              m-(3-pyrazole-CO)                                                                             m-(3-pyrazole-CO)                                                                              +++ +++      695                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15AA                                                                              RSSR                                                                              m-(ClCH.sub.2 C(O)NH                                                                          m-(ClCH.sub.2 C(O)NH                                                                           +++ +++            51                        C(O)NH)C.sub.6 H.sub.4 CH.sub.2                                                               C(O)NH)C.sub.6 H.sub.4 CH.sub.2                       15AB                                                                              RSSR                                                                              m-H.sub.2 NC.sub.6 H.sub.4 CH.sub.2.HCl                                                       m-isonicotinamido-                                                                             +++ +++ 208 (dec)                                                                          642    4                                        C.sub.6 H.sub.4 CH.sub.2 HCl                          15AC                                                                              RSSR                                                                              m-isonicotinamido-                                                                            m-isonicotinamido-                                                                             +++ +++ 205 (dec)                                                                          747   47                        C.sub.6 H.sub.4 CH.sub.2.HCl                                                                  C.sub.6 H.sub.4 CH.sub.2.HCl                          15AD                                                                              RSSR                                                                              m-((CH.sub.3).sub.2 NCH.sub.2 CH.sub.2                                                        m-CH.sub.3 C(O)C.sub.6 H.sub.4 CH.sub.2                                                        +++ +++ 170 (dec)                                                                          646    4                        C(O)C.sub.6 H.sub.4 CH.sub.2                                          15AE                                                                              RSSR                                                                              m-((CH.sub.3).sub.2 NCH.sub.2 CH.sub.2                                                        m-((CH.sub.3).sub.2 NCH.sub.2 CH.sub.2                                                         +++ +++ 164 (dec)                                                                          701   43                        C(O)C.sub.6 H.sub.4 CH.sub.2                                                                  C(O)C.sub.6 H.sub.4 CH.sub.2                          15AF                                                                              RSSR                                                                              m-(H.sub.2 NC(NOH))                                                                           cyclopropylmethyl                                                                              +++ +++ 183-186                                                                            529   44                        C.sub.6 H.sub.4 CH.sub.2                                              15AG                                                                              RSSR                                                                              m,p-dihydroxy-  cyclopropylmethyl                                                                              +++ +++ 141  503    2                        C.sub.6 H.sub.4 CH.sub.2                                              15AH                                                                              RSSR                                                                              m-(H.sub.2 NC(NOH))-                                                                          p-hydroxymethyl- +++ +++ 198-199                                                                            595   44                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15AI                                                                              RSSR                                                                              p-(H2NC(NOH))   p-hydroxymethyl  ++  +++ 215  595   44                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15AJ                                                                              RSSR                                                                              m-(5-amino-     m-(5-amino-      +++ +++ 208-209                                                                            690   49                        1,3,4-oxadiazo- 1,3,4-oxadiazo-                                               2-yl)-C.sub.6 H.sub.4 CH.sub.2                                                                2-yl)-C.sub.6 H.sub.4 CH.sub.2                        15AK                                                                              RSSR                                                                              m-hydrazide-    cyclopropylmethyl                                                                              +++ +++ 176-177                                                                            529   48                        C.sub.6 H.sub.4 CH.sub.2                                              15AL                                                                              RSSR                                                                              m-((CH.sub.3).sub.3 COC(O)                                                                    m-((CH.sub.3).sub.3 COC(O)                                                                     ++  +++ 227-228                                                                            808   50                        NHNCHC.sub.6 H.sub.4 CH.sub.2                                                                 NHNCHC.sub.6 H.sub.4 CH.sub.2                         15AM                                                                              RSSR                                                                              m-(C.sub.2 H.sub.5 OC(O))                                                                     m-(5-amino-                   661   53                        C.sub.6 H.sub.4 CH.sub.2                                                                      1,3,4-oxadiazo-                                                               2-yl)-C.sub.6 H.sub.4 CH.sub.2                        15AN                                                                              RSSR                                                                              m-(H2NC(NOH))   2-naphthylmethyl +++ +++ 192-193                                                                            615   44                        C.sub.6 H.sub.4 CH.sub.2                                              15AO                                                                              RSSR                                                                              3-((5-(CH.sub.3).sub.2 NCH.sub.2)                                                             3-((5-(CH.sub.3).sub.2 NCH.sub.2)                                                              +++ +++ 165 (dec)  56                1,2,4-oxadiazol                                                               1,2,4-oxadiazol                                                                       yl)-C.sub.6 H.sub.4 CH.sub.2.                                                                 yl)-C.sub.6 H.sub.4 CH.sub.2.                                 HCl             HCl                                                   15AP                                                                              RSSR                                                                              m-(N-methyl-N'- H                +       147-149                                                                            467    2                        piperazinyl)                                                                  propyl.HCl                                                            15AQ                                                                              RSSR                                                                              m-cyanoC.sub.6 H.sub.4 CH.sub.2                                                               p-hydroxyC.sub.6 H.sub.4 CH.sub.2                                                              +++ +++      548   54                15AR                                                                              RSSR                                                                              m-cyanoC.sub.6 H.sub.4 CH.sub.2                                                               m-3-pyridylmethyl                                                                              +++ +++      533   55                15AS                                                                              RSSR                                                                              m-(N-methyl-N'- H                +   +/++                                                                              150  467    2                        piperazinyl)                                                                  propyl.HCl                                                            15AT                                                                              RSSR                                                                              m-(H.sub.2 NC(NOH))                                                                           H                +++ +++ 172-179                                                                            475    2                        C.sub.6 H.sub.4 CH.sub.2                                              15AU                                                                              RSSR                                                                              m-(H.sub.2 NC(NOH))                                                                           p-hydroxyC.sub.6 H.sub.4 CH.sub.2                                                              +++ +++ 195-197                                                                            581   44                        C.sub.6 H.sub.4 CH.sub.2                                              15AV                                                                              RSSR                                                                              m-(H.sub.2 NC(NOH))                                                                           p-benzyloxy-     ++      180-182                                                                            671   44                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15AW                                                                              RSSR                                                                              m-(H.sub.2 NC(NOH))                                                                           4-pyridylmethyl          178-192                                                                            566   44                        C.sub.6 H.sub.4 CH.sub.2                                              15AX                                                                              RSSR                                                                              m-(2-           m-(2-            ++      205  739   46                        benzimidazolyl)-                                                                              benzimidazolyl)-                                              C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15AY                                                                              RSSR                                                                              m-(2-           m-(2-            ++      217-219                                                                            739   46                        benzimidazolyl)-                                                                              benzimidazolyl)-                                              C.sub.6 H.sub.4 CH.sub.2.HCl                                                                  C.sub.6 H.sub.4 CH.sub.2.HCl                          15AZ                                                                              RSSR                                                                              m-(CH.sub.3 NHC(NOH))                                                                         m-(CH.sub.3 NHC(NOH))                                                                          +++ +++ 192 (dec)                                                                          651   46                        CC.sub.6 H.sub.4 CH.sub.2                                                                     C.sub.6 H.sub.4 CH.sub.2                              15BA                                                                              RSSR                                                                              m-(C.sub.3 H.sub.7 NHC(NOH))                                                                  m-(C.sub.3 H.sub.7 NHC(NOH))                                                                   +++ +++ 177  707   46                        C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15BB                                                                              RSSR                                                                              m-(2-amino-     m-(2-amino-      ++      226-227                                                                            693   45                        pyrimidin-4-yl)-                                                                              pyrimidin-4-yl)-                                              C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15BC                                                                              RSSR                                                                              cyclopropylmethyl                                                                             4-fluoro-3-cyano-                                                                              ++           514   44                                        C.sub.6 H.sub.4 CH.sub.2                              15BD                                                                              RSSR                                                                              m-(2-amino-4-   m-(2-amino-4-    +++ +++ 151-160                                                                            703                             thienyl)-C.sub.6 H.sub.4 CH.sub.2                                                             thienyl)-C.sub.6 H.sub.4 CH.sub.2                     15BE                                                                              RSSR                                                                              cyclopropylmethyl                                                                             m-(2-amino-4-    +++ +++ 118-127                                                                            569                                             thienyl)-C.sub.6 H.sub.4 CH.sub.2                     15BF                                                                              RSSR                                                                              m-(2-chloromethyl                                                                             m-(2-chloromethyl                                                                              ++  ++  178-181                                                                            503                     2-propenyl)-                                                                  2-propenyl)-                                                                          C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15BG                                                                              RSSR                                                                              m-              m-               +       73-80                                                                              467                             (2-hydroxymethyl                                                                              (2-hydroxymethyl                                      2-propenyl)-                                                                  2-propenyl)-                                                                          C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15BH                                                                              RSSR                                                                              cyclopropylmethyl                                                                             ((2-             +++ +++ 155-164                                                                            643                                             benzimidazolyl)-                                                              CH.sub.2 NHC(O))                                                              C.sub.6 H.sub.4 CH.sub.2                              15BI                                                                              RSSR                                                                              m-(benzyloxy    m-(benzyloxy     +++ +++      803.5                           methylcarbonyl)-                                                                              methylcarbonyl)-                                              C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15BJ                                                                              RSSR                                                                              m-(1-SEM-5-     m-(1-SEM-5-      +++ +++      899.5                           imidazoyl)-     imidazoyl)-                                                   C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15BK                                                                              RSSR                                                                              m-(5-imidazoyl)-                                                                              m-(5-imidazoyl)- +++ +++ 171-175                                                                            639                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15BL                                                                              RSSR                                                                              m-(5-imidazoyl)-                                                                              m-(5-imidazoyl)- +++ +++                                      C.sub.6 H.sub.4 CH.sub.2 .HCl                                                                 C.sub.6 H.sub.4 CH.sub.2 .HCl                         15BM                                                                              RSSR                                                                              m-(1-(N,N-dimethyl                                                                            m-(1-(N,N-dimethyl                                                                             ++  +++      853                             sulfamoyl)-2-   sulfamoyl)-2-                                                 imidazoyl)-     imidazoyl)-                                                   C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15BN                                                                              RSSR                                                                              m-(4-pyrazole)- m-(4-pyrazole)-  +++ +++                                      C.sub.6 H.sub.4 CH.sub.2 .HCl                                                                 C.sub.6 H.sub.4 CH.sub.2 .HCl                         15BP                                                                              RSSR                                                                              m-carbomethoxy- m-(3-pyrazole)-  +++ +++ 127-130                                                                            631.4                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15BQ                                                                              RSSR                                                                              m-hydroxymethyl-                                                                              m-(3-pyrazole)-  +++ +++      603.2                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15BR                                                                              RSSR                                                                              m-(2-imidazoyl)-                                                                              m-(2-imidazoyl)- +++ +++ 178-180                                                                            639.4                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15BS                                                                              RSSR                                                                              m-(2-imidazoyl)-                                                                              m-(2-imidazoyl)- +++ +++ 191-194                              C.sub.6 H.sub.4 CH.sub.2 .HCl                                                                 C.sub.6 H.sub.4 CH.sub.2 .HCl                         15BT                                                                              RSSR                                                                              m-((2-morpholino                                                                              m-(3-pyrazole)-  +++ +++      729.5                           ethyl)amino     C.sub.6 H.sub.4 CH.sub.2                                      carbonyl)-C.sub.6 H.sub.4 CH.sub.2                                    15BU                                                                              RSSR                                                                              3-pyridinylmethyl                                                                             m-(3-pyrazole)-  +++ +++ 133-136                                                                            574.2                                           C.sub.6 H.sub.4 CH.sub.2                              15BV                                                                              RSSR                                                                              m-cyano-C.sub.6 H.sub.4 CH.sub.2                                                              m-(3-pyrazole)-  +++ +++      598.2                                           C.sub.6 H.sub.4 CH.sub.2                              15BW                                                                              RSSR                                                                              m-(H2NC(NOH))   m-(3-pyrazole)-  +++ +++                                      C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15BX                                                                              RSSR                                                                              H               m-(3-pyrazole)-  +++ +++      483.2                                           C.sub.6 H.sub.4 CH.sub.2                              15BY                                                                              RSSR                                                                              p-(benzyloxy)-  m-(3-pyrazole)-  +++ +++      679.3                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15BZ                                                                              RSSR                                                                              m-((3-pyridinyl m-(3-pyrazole)-  +++ +++      707.5                           methyl)amino    C.sub.6 H.sub.4 CH.sub.2                                      carbonyl)-C.sub.6 H.sub.4 CH.sub.2                                    15CA                                                                              RSSR                                                                              p-hydroxy-C.sub.6 H.sub.4 CH.sub.2                                                            m-(3-pyrazole)-  +++ +++ 150-153                                                                            589.3                                           C.sub.6 H.sub.4 CH.sub.2                              15CB                                                                              RSSR                                                                              m-((2-pyridinyl m-(3-pyrazole)-  +++ +++      707                             methyl)amino    C.sub.6 H.sub.4 CH.sub.2                                      carbonyl)-C.sub.6 H.sub.4 CH.sub.2                                    15CC                                                                              RSSR                                                                              m,p-dihydroxy-  m-(3-pyrazole)-  +++ +++ 177-180                                                                            622                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15CD                                                                              RSSR                                                                              m-nitro-C.sub.6 H.sub.4 CH.sub.2                                                              m-(3-pyrazole)-  +++ +++      (635)                                           C.sub.6 H.sub.4 CH.sub.2                              15CE                                                                              RSSR                                                                              m-amino-C.sub.6 H.sub.4 CH.sub.2                                                              m-(3-pyrazole)-  +++ +++ 136-138                                                                            605                                             C.sub.6 H.sub.4 CH.sub.2                              15CF                                                                              RSSR                                                                              m-cyano-p-fluoro-                                                                             m-(3-pyrazole)-  +++ +++ 118-120                                                                            616                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15CG                                                                              RSSR                                                                              H               m-(3-pyrazole)-  +++ +++ 152-154                                              C.sub.6 H.sub.4 CH.sub.2 .HCl                         15CH                                                                              RSSR                                                                              m-acetyl-C.sub.6 H.sub.4 CH.sub.2                                                             m-(CH.sub.3 C(NOH)       186-188                                                                            606.4                                           C.sub.6 H.sub.4 CH.sub.2                              15CI                                                                              RSSR                                                                              m-acetyl-p-fluoro                                                                             m-acetyl-p-fluoro        203-204                                                                            649.3                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2      (M + Na)                15CJ                                                                              RSSR                                                                              m-cyano-p-fluoro-                                                                             m-acetyl-p-fluoro        192-193                                                                            632.3                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2      (M + Na)                15CK                                                                              RSSR                                                                              m-(CH.sub.3 C(NOH))                                                                           m-(CH.sub.3 C(NOH))           621.4                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15CL                                                                              RSSR                                                                              m-(CH.sub.3 C(NOH))                                                                           m-(CH.sub.3 C(NOH))           657.3                           p-fluoro-C.sub.6 H.sub.4 CH.sub.2                                                             p-fluoro-C.sub.6 H.sub.4 CH.sub.2                     15CM                                                                              RSSR                                                                              m-(H.sub.2 NC(NOH))                                                                           m-(H.sub.2 NC(NOH))           658.4                           p-fluoro-C.sub.6 H.sub.4 CH.sub.2                                                             p-fluoro-C.sub.6 H.sub.4 CH.sub.2                     15CN                                                                              RSSR                                                                              2-naphthylmethyl                                                                              5-methyl-5-      +++ +++      627                                             carbomethoxy                                                                  hexyl                                                 15CO                                                                              RSSR                                                                              2-naphthylmethyl                                                                              5-methyl-5-      +++ +++      595                                             carbohexyl                                            15CP                                                                              RSSR                                                                              5,5-dimethyl-6- 5,5-dimethyl-6-  ++  +++      583                             hydroxymethyl   hydroxymethyl                                         15CQ                                                                              RSSR                                                                              p-aminobenzyl   p-aminobenzyl    +++ +++ 114-116                      15CS                                                                              RSSR                                                                              5-benzimidazolyl                                                                              5-benzimidazolyl ++  ++  209-212                              methyl          methyl                                                15CT                                                                              RSSR                                                                              5-benzotriazolyl                                                                              5-benzotriazolyl +++ +++ >310                                 methyl          methyl                                                15CU                                                                              RSSR                                                                              3-hydroxy-5-    3-hydroxy-5-     ++      185-192                              benzotriazolyl  benzotriazolyl                                                methyl          methyl                                                15CV                                                                              RSSR                                                                              2-oxo-5-        2-oxo-5-         +++ ++  240-245                              benzimidazolyl- benzimidazolyl-                                               methyl          methyl                                                15CW                                                                              RSSR                                                                              5-(2,2-dioxo-   5-(2,2-dioxo-    +++ ++  210 (dec)                            benz-2,1,3-     benz-2,1,3-                                                   thiadiazolyl)-  thiadiazolyl)-                                                methyl          methyl                                                15CX                                                                              RSSR                                                                              5-indazolylmethyl                                                                             5-indazolylmethyl                                                                              +++ +++ 165-170                      15CY                                                                              RSSR                                                                              6-indazolylmethyl                                                                             6-indazolylmethyl                                                                              +++ +++ 170-175                      15CZ                                                                              RSSR                                                                              (3-methyl-2-oxo-                                                                              (3-methyl-2-oxo- +++ +++ 192-200                              5-benzimidazolyl)                                                                             5-benzimidazolyl)                                     methyl                                                                        methyl                                                                        15DA                                                                              RSSR                                                                              5-isatinylmethyl                                                                              5-isatinylmethyl +++ +++ 196-200                      15DB                                                                              RSSR                                                                              (3-hydroxyimino-5-                                                                            (3-hydroxyimino-5-                                                                             +++ +++ 242-245                              oxindolyl)methyl                                                                              oxindolyl)methyl                                      15DC                                                                              RSSR                                                                              (2-oxo-5-benz   (2-oxo-5-benz    +++ +++ 181-185                              oxazolin-2-yl)- oxazolin-2-yl)-                                               methyl          methyl                                                15DD                                                                              RSSR                                                                              5-oxindolylmethyl                                                                             5-oxindolylmethyl                                                                              +++ +++ 170-175                      15DE                                                                              RSSR                                                                              5-indolylmethyl 5-indolylmethyl  +++ +++ 170 (dec)                    15DF                                                                              RSSR                                                                              (3-amino-5-     (3-amino-5-      +++ +++ 180-184                              indazolyl)methyl                                                                              indazolyl)methyl                                      15DG                                                                              RSSR                                                                              (3-amino-5-     (3-amino-5-      +++ +++ 153-158                              benzisoxazolyl) benzisoxazolyl)                                               methyl          methyl                                                15DH                                                                              RSSR                                                                              (3-methylamino-5-                                                                             (3-methylamino-5-                                                                              +++ +++ 174-177                              indazolyl)methyl                                                                              indazolyl)methyl                                      15DI                                                                              RSSR                                                                              (3-chloro-5-    (3-chloro-5-     +++ +++ 290 (dec)                            indazolyl)methyl                                                                              indazolyl)methyl                                      15DJ                                                                              RSSR                                                                              (3-ethylamino-5-                                                                              (3-ethylamino-5- +++ +++ 158-162                              indazolyl)methyl                                                                              indazolyl)methyl                                      15DK                                                                              RSSR                                                                              (3-methylamino-5-                                                                             (3-methylamino-5-                                                                              +++     150-153                              benzisoxazolyl) benzisoxazolyl)                                               methyl          methyl                                                15DL                                                                              RSSR                                                                              (3-isopropylamino-                                                                            (3-isopropylamino-                                                                             +++     147-152                              5-indazolyl)    5-indazolyl)                                                  methyl          methyl                                                15DM                                                                              RSSR                                                                              H               5-benzotriazolyl +++     188-190                                              methyl                                                15DN                                                                              RSSR                                                                              benzyl          5-benzotriazolyl +++ +++ 268-270                                              methyl                                                15DO                                                                              RSSR                                                                              2-naphthylmethyl                                                                              5-benzotriazolyl +++ +++ 155-159                                              methyl                                                15DP                                                                              RSSR                                                                              cyclopropylmethyl                                                                             5-benzotriazolyl +++ +++ 146-150                                              methyl                                                15DQ                                                                              RSSR                                                                              p-hydroxymethyl 5-benzotriazolyl +++ +++ 151-153                              C.sub.6 H.sub.4 CH.sub.2                                                                      methyl                                                15DR                                                                              RSSR                                                                              m-hydroxyC.sub.6 H.sub.4 CH.sub.2                                                             5-benzotriazolyl +++ +++ 296-298                                              methyl                                                15DS                                                                              RSSR                                                                              m-(3-pyrazolyl) 5-benzotriazolyl +++ +++ 183-186                              C.sub.6 H.sub.4 CH.sub.2                                                                      methyl                                                15DT                                                                              RSSR                                                                              m-iodoC.sub.6 H.sub.4 CH.sub.2                                                                5-benzotriazolyl     +++ 153-156                                              methyl                                                15DU                                                                              RSSR                                                                              m-cyanomethyl   m-cyanomethyl    ++  +++      585.2                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15DV                                                                              RSSR                                                                              m-(H.sub.2 NC(O)(CH.sub.2)                                                                    m-(H.sub.2 NC(O)(CH.sub.2)                                                                     +++ +++      621.4                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15DW                                                                              RSSR                                                                              m-(carbomethoxy m-(carbomethoxy  +++ +++      651.4                           methyl)-C.sub.6 H.sub.4 CH.sub.2                                                              methyl)-C.sub.6 H.sub.4 CH.sub.2                      15DX                                                                              RSSR                                                                              m-              m-               +++ +++      595.4                           (2-hydroxyethyl)-                                                                             (2-hydroxyethyl)-                                             C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15DY                                                                              RSSR                                                                              o-hydroxy-      o-hydroxy-       +++ +++      539.3                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15DZ                                                                              RSSR                                                                              H               m-(methylamino)- +++ +++      500.2                                           p-fluoroC.sub.6 H.sub.4 CH.sub.2                      15EA                                                                              RSSR                                                                              o-hydroxy-      p-hydroxymethyl  +++ +++      553.3                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15EB                                                                              RSSR                                                                              o-hydroxy-      m-hydroxymethyl  ++  +++      553.3                           C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15EC                                                                              RSSR                                                                              m-cyano-p-fluoro-                                                                             m-cyano-p-fluoro-                                                                              ++  +++      (610.2)                         C.sub.6 H.sub.4 CH.sub.2                                                                      C.sub.6 H.sub.4 CH.sub.2                              15ED                                                                              RSSR                                                                              m-(H.sub.2 NC(O))-p-                                                                          m-(H.sub.2 NC(O))-p-                                                                           +++ +++      (646.4)                         fluoro-C.sub.6 H.sub.4 CH.sub.2                                                               fluoro-C.sub.6 H.sub.4 CH.sub.2                       15EE                                                                              RSSR                                                                              m-carbomethoxy-p-                                                                             m-carbomethoxy-p-                                                                              +++ +        (676.3)                         fluoro-C.sub.6 H.sub.4 CH.sub.2                                                               fluoro-C.sub.6 H.sub.4 CH.sub.2                       15EF                                                                              RSSR                                                                              m-(H.sub.2 NC(NOH))                                                                           m-(H.sub.2 NC(NOH))                                                                            +++ +++      659.1                           p-fluoroC.sub.6 H.sub.4 CH.sub.2                                                              p-fluoroC.sub.6 H.sub.4 CH.sub.2                      15EG                                                                              RSSR                                                                              m-(hydroxymethyl)                                                                             m-(hydroxymethyl)                                                                              +++ +++      603.3                           p-fluoroC.sub.6 H.sub.4 CH.sub.2                                                              p-fluoroC.sub.6 H.sub.4 CH.sub.2                      15EH                                                                              RSSR                                                                              m-(H.sub.2 NC(O))                                                                             m-(H.sub.2 NC(NOH))                                                                            +++ +++      644.0                           p-fluoroC.sub.6 H.sub.4 CH.sub.2                                                              p-fluoroC.sub.6 H.sub.4 CH.sub.2                      15EI                                                                              RSSR                                                                              p-methylC.sub.6 H.sub.4 CH.sub.2                                                              p-hydroxymethyl- +++     174-175                                                                            551                                             C.sub.6 H.sub.4 CH.sub.2                              15EJ                                                                              RSSR                                                                              5-hydroxy-5-    5-hydroxy-5-     ++  ++       555                             methylhexyl     methylhexyl                                           15EK                                                                              RSSR                                                                              5-(methylamino  5-(methylamino   ++  ++       613                             carbonyloxy)    carbonyloxy)                                                  pentyl          pentyl                                                15EL                                                                              RSSR                                                                              7-(1,1,4,4-tetra                                                                              7-(1,1,4,4-tetra +   ++/+     727                             methyl-1,2,3,4- methyl-1,2,3,4-                                               tetrahydro      tetrahydro                                                    naphthyl)methyl naphthyl)methyl                                       15EM                                                                              RSSR                                                                              5-azidopentyl   5-azidopentyl    ++  +++      549                                                                           (566)                   15EN                                                                              RSSR                                                                              5-(methylsulfonyl                                                                             5-(methylsulfonyl                                                                              ++  ++/+     (670)                           amino)-pentyl   amino)-pentyl                                         15EO                                                                              RSSR                                                                              5-(p-methylphenyl                                                                             5-(p-methylphenyl                                                                              ++  ++/+     (822)                           sulfonyl)pentyl sulfonyl)pentyl                                       15EP                                                                              RSSR                                                                              5-aminopentyl   5-aminopentyl    +   ++/+     497                     15EQ                                                                              RSSR                                                                              5-methoxycarbonyl                                                                             5-methoxycarbonyl                                                                              ++  ++/+     (630)                           aminopentyl     aminopentyl                                           15ER                                                                              RSSR                                                                              5-(phenylamino  5-(phenylamino   ++  ++/+                                     carbonylamino)  carbonylamino)                                                pentyl          pentyl                                                15ES                                                                              RSSR                                                                              5-(methylamino  5-(methylamino   ++  ++/+     611                             carbonylamino)  carbonylamino)                (628)                           pentyl          pentyl                                                15ET                                                                              RSSR                                                                              5-(acetylamino) 5-(acetylamino)  ++  ++/+     (598)                           pentyl          pentyl                                                15EU                                                                              RSSR                                                                              5-((3-pyridinyl 5-((3-pyridinyl  +++ +++      767                             methoxy)carbonyl                                                                              methoxy)carbonyl                                              amino)pentyl.HCl                                                                              amino)pentyl.HCl                                      15EV                                                                              RSSR                                                                              5-((methylamino)                                                                              5-((methylamino) ++  ++/+     643                             thiocarbonyl    thiocarbonyl                                                  amino)-pentyl   amino)-pentyl                                         15EW                                                                              RSSR                                                                              5-((phenylamino)                                                                              5-((phenylamino) ++  ++/+     767                             thiocarbonyl    thiocarbonyl                                                  amino)-pentyl   amino)-pentyl                                         15EX                                                                              RSSR                                                                              5-(benzoylamino)-                                                                             5-(benzoylamino)-                                                                              ++  ++/+     (722)                           pentyl          pentyl                                                15EY                                                                              RSSR                                                                              5-((3-fluoro    5-((3-fluoro     ++  +++      741                             benzoyl)amino)- benzoyl)amino)-                                               pentyl          pentyl                                                15EZ                                                                              RSSR                                                                              5-(N-methylglycyl                                                                             5-(N-methylglycyl                                                                              ++  ++/+     639                             amino)pentyl.HCl                                                                              amino)pentyl.HCl                                      15FA                                                                              RSSR                                                                              5-(4-pyridinyl  5-(4-pyridinyl   ++  +++      707                             carbonylamino)- carbonylamino)-                                               pentyl.HCl      pentyl.HCl                                            15FB                                                                              RSSR                                                                              5-((2-fluoro    5-((2-fluoro     ++  +++      741                             benzoyl)amino)- benzoyl)amino)-               (758)                           pentyl          pentyl                                                15FC                                                                              RSSR                                                                              5-((4-fluoro    5-((4-fluoro     ++  ++/+     741                             benzoyl)amino)- benzoyl)amino)-               (758)                           pentyl          pentyl                                                15FD                                                                              RSSR                                                                              4-cyanobutyl    4-cyanobutyl     ++  ++       489                                                                           (506)                   15FE                                                                              RSSR                                                                              5-(4-morpholinyl                                                                              5-(4-morpholinyl ++  ++/+     751                             methylcarbonyl  methylcarbonyl                                                amino)-pentyl.HCl                                                                             amino)-pentyl.HCl                                     15FF                                                                              RSSR                                                                              5-(2-pyrazinyl  5-(2-pyrazinyl   +   ++/+     (726)                           carbonylamino)- carbonylamino)-                                               pentyl          pentyl                                                15FG                                                                              RSSR                                                                              5-((3,5-difluoro                                                                              5-((3,5-difluoro ++  ++/+     (794)                           benzoyl)amino)- benzoyl)amino)-                                               pentyl          pentyl                                                15FH                                                                              RSSR                                                                              4-(dimethylamino)                                                                             4-(dimethylamino)                                                                              ++  ++/+     525                             butyl.HCl       butyl.HCl                                             15FI                                                                              RSSR                                                                              4-aminobutyl.HCl                                                                              4-aminobutyl.HCl +   ++/+     469                     15FJ                                                                              RSSR                                                                              5-((3-trifluoro 5-((3-trifluoro  ++  ++/+     841                             methylbenzoyl)  methylbenzoyl)                                                amino)-         amino)-                                                       pentyl          pentyl                                                15FK                                                                              RSSR                                                                              4-(1-imidazolyl)-                                                                             4-(1-imidazolyl)-                                                                              +            599                             pentyl.HCl      pentyl.HCl                                            15FL                                                                              RSSR                                                                              5-(1-pyrazolyl)-                                                                              5-(1-pyrazolyl)- +            599                             pentyl          pentyl                                                15FM                                                                              RSSR                                                                              5-(4-morpholinyl)                                                                             5-(4-morpholinyl)                                                                              +            637                             pentyl.HCl      pentyl.HCl                                            15FN                                                                              RSSR                                                                              3-furylmethyl   3-furylmethyl    +++ +++ 152.5-                                                                        153                          15FO                                                                              RSSR                                                                              3-furylmethyl   (5-carbonyl-3-           oil                                                  furyl)methyl                                          15FP                                                                              RSSR                                                                              (5-hydroxymethyl-                                                                             (5-hydroxymethyl-                                                                              +++                                          3-furyl)-methyl 3-furyl)-methyl                                       15FQ                                                                              RSSR                                                                              (5-hydroxyimino (5-hydroxyimino  +++ +++                                      methyl-3-furyl)-                                                                              methyl-3-furyl)-                                              methyl          methyl                                                15FR                                                                              RSSR                                                                              3-furylmethyl   (5-hydroxymethyl-                                                                              +++ +++                                                      3-furyl)-methyl                                       15FS                                                                              RSSR                                                                              (2,5-dihydro)-3-                                                                              (2,5-dihydro)-3- ++                                           thienylmethyl   thienylmethyl                                         15FT                                                                              RSSR                                                                              3-thienylmethyl 3-thienylmethyl  +++          519                     15FU                                                                              RSSR                                                                              (1,1-dioxo-2,5- (1,1-dioxo-2,5-  +                                            dihydro-3-      dihydro-3-                                                    thienyl)-methyl thienyl)-methyl                                       15FV                                                                              RSSR                                                                              2-furylmethyl   H                +++                                  15FW                                                                              RSSR                                                                              2-furylmethyl   2-furylmethyl    +++                                  15FX                                                                              RSSR                                                                              2-methylene-3-  2-methylene-3-   ++                                           butenyl         butenyl                                               15FY                                                                              RSSR                                                                              5-hydroxymethyl-                                                                              5-hydroxymethyl- ++                                           2-furylmethyl   2-furylmethyl                                         __________________________________________________________________________

Notes (for Table 2d):

(1) Prepared according to the general alkylation procedure.

(2) Monoalkylated compounds were prepared by following the procedure 5under the title of synthesis of monoalkyl cyclic urea. Furtherfunctional group elaboration is similar to the corresponding dialkylatedcyclic ureas described herein.

(3) Prepared by the alkylating the appropriate monoalkylated compound.Further functional group elaboration is similar to the correspondingdialkylated compounds described herein.

(4) Isolated as the side product due to incomplete reaction.

(5) Methoxylamine hydrochloride (92 mg, 1.08 mmol) was added tobis(N-m-benzaldehyde) cyclic urea (100 mg, 0.18 mmol) in a mixture of 2mL pyridine and 2 mL ethanol. The mixture was heated to reflux for 4 hrand the solvent was removed on a rotary evaporator. The residue waspurified on silica gel (0.2:3:7 methanol:ethyl acetate:methylenechloride) to provide the product (93 mg) in 83% yield. Other amines suchas, but not limited to, hydrazine and semicarbazides, can be usedinstead of methoxylamine. E.g. hydroxylamine was used to makeformaldoxime as in 6C in Table 2C.

(6) Preparation of monoacyl compounds were favored by using oneequivalent of acylating agent.

(7) A solution of bis(N-m-benzoic acid) cyclic urea (1.2 g, 1.56 mmol)in 1:1 benzene: methylene chloride containing 1 drop of DMF and pyridine(0.75 mL, 9.36 mmol) was treated with oxalyl chloride (2M in methylenechloride, 4.87 mL, 9.36 mmol) at zero degree and stirred at roomtemperature for overnight. The solvent removed on a rotary evaporatorand the resulting residue was dried under pump for 2 hr. To the residue20 mL methylene chloride was added followed by pyridine (0.75 mL,9.36mmol) and methylamine (8.03M in ethanol, 1.17 mL, 9.36 mmol). Stirred atroom temperature for overnight. The mixture was extracted with EtOAc,dried over MgSO₄ and purified on silica gel (1:9 methanol chloroform).Following the same hydrolysis procedure, the product (66 mg) wasisolated in 68% yield. Other alkylamines or ammonia can be used insteadof methylamine.

(8) A solution of bis(N-m-hydroxy-benzyl)cyclic urea (500 mg, 0.93 mmol)in methylene chloride was treated with triethylamine (0.23 mL, 1.67mmol) at -20° C. Then a solution of 1-adamantyl isocyanate (252 mg, 1.4mmol) in 5 mL methylene chloride was added dropwise. The mixture wasstirred at -20° C. for 10 min, 0° C. for 1 hr, room temperature forovernight and washed with cooled 5% HCl, sat'd NaHCO3, water, and driedover MgSO4. The residue was purified on silica gel (2:8 ethylacetate:methylene chloride). The product was isolated (150 mg) in 18%yield. Other acylating agents besides isocyanates can be used.

(9) 2 drops of OsO₄ (25% in t-BuOH) was added into the mixture ofbis(N-m-allyloxy-benzyl) cyclic urea (120 mg, 0.19 mmol) andN-methyl-morpholine N-oxide (77 mg, 0.57 mmol) in 5 mL acetone. Themixture was stirred at RT for overnight. The solvent was removed on atotary evaporator and the residue was purified on silica gel (2:8methanol:chloroform). The product was isolated (145 mg) in 100% yield.

(10) The ethyl ester was prepared by refluxing the appropriate acid with4M HCl (in dioxane) in ethanol.

(11) To the appropriate ethyl ester (139 mg, 0.21 mmol) andhydroxylamine hydrochloride (118 mg, 1.71 mmol) mixture (10 mL methanolwas used as the solvent), a 5M (2.4 mL, 2.1 mmol) solution of potassiumhydroxide in methanol was added dropwisely at room temperature. Afterstirring for 24 hr, methanol was evaporated and the solid residueacidified with acetic acid and extracted with ethyl acetate which waspurified on silica gel (0.1:3:7 acetic acid:methanol:ethyl acetate). Theproduct was isolated (90 mg) in 69% yield

(12) To the bis(N-m-allyloxy-benzyl) cyclic urea (100 mg, 0.16 mmol) in10 mL methanol, ozone was bubbled through for 10 min at -78° C. Afterwarmed up to RT, sodium borohydride (60.5 mg, 1.6 mmol) was added andstirred at RT for overnight. The reaction was worked up by quenchingwith acetic acid, the solvent was removed on rotary evaporator andpurified on silica gel (0.3:9.7 methanol:ethyl acetate). The product wasisolated (88 mg) in 88% yield.

(13) A solution of the bis-cyano compound (400 mg, 0.55 mmol) inabsolute methanol was saturated with hydrochloric acid and left at zerodegree for 3 hr followed by TLC until completed. After evaporation ofthe solvent, the resulting was solubilized in 2M ammonia in methanol.After one week stirring at room temperature, the solvent was removedunder reduced pressure and the residue was purified on silica gel (by0.2:1:9 acetic acid:methanol:ethyl acetate) to give a solid. The overallyield was 53% (171 mg).

(14) To the bis(N-p-hydroxy-benzyl) cyclic urea (600 mg, 1.11 mmol) inethanol, NaOH (622 mg, 15.54 mmol) in 2 mL water was added dropwise. Themixture was heated up to 80° C. for 1 hr, then 2 mL chloroform was addedfollowing additional heating at 80° C. for overnight. The reaction wasworked up by neutralizing with 5% cooled HCl, washed with sat'd sodiumbicarbonate, water and dried over MgSO₄. The residue was purified onsilica gel (1.5:8.5 methanol:chloroform) to give 11E as a solid (59 mg,11%). To this solid, ethanol was added followed by excess sodiumborohydride (10 equiv). The mixture was heated up to reflux for 2 hr.The reaction was worked up by quenching with acetic acid, the solventwas removed on rotary evaporator and the purified on silica gel (2:8methanol:chloroform). The product was isolated (36 mg) in 63% yield.

(15) n-Butyllithium (1.6M in hexane, 1.6 mL, 2.5 mmol) was addeddropwise to bis(N-m-bromo-benzyl) cyclic urea (840 mg, 1 mmol) in THF at-78° C. After stirring for 0.5 hr, trimethyl borate (0.58 mL, 5 mmol)was added. The mixture slowly warmed up to room temperature and remainedstirring for 4 hr. The reaction mixture was decomposed by the additionof 5% HCl, diluted with ethyl acetate, washed 2 time with water anddried over MgSO₄. The residue was purified on silica gel (0.1:0.5:9.5acetic acid:methanol:chloroform). Following the same hydrolysisprocedure, the product was isolated (176 mg) in 53% yield.

(16) Required alkylating agents were prepared in a three step sequence:1.) Asymmetric cyclopropanation D. A. Evans et al., J. Amer. Chem. Soc.1991 , 113 , 726-728!. 2.) Reduction with lithium aluminum hydride. 3.)Conversion to the bromide with CBr₄, Ph₃ P, and imidazole.

(17) Prepared from Example 15J using the conditions described forExample 6ZI in Table 2C.

(18) Prepared from the compound of Table 2C, Example 6ZI usingmethanesulfonic anhydride.

(19) Prepared from Example 6ZI using isocyanic acid.

(20) A solution (60 ml) of borane in tetrahydrofuran (THF, 2M) was addeddropwise into a cooled solution (0° C.) of bis-formamide 6ZM (9.18 g,15.5 mmoles) in anhydrous THF (200 ml). The mixture was stirred for 16hours at room temperature, followed by dropwise addition of methanol (50ml). When the effervescence had subsided, hydrochloric acid (conc., 35ml) was added. The residue was stirred for 30 minutes, evaporated todryness, and partitioned between ethyl acetate and sodium hydroxide(1N). The organic layer was washed with brine, dried over magnesiumsulfate, filtered and evaporated to give 8.65 g of the product.

(21) Prepared from Example 6ZI using benzyl chloroformate.

(22) Prepared from Example 15D using the conditions described of 6ZM.

(23) Prepared from Example 15H using the conditions described forExample 6ZI.

(24) Prepared from Example 15F using the procedure described for Example15D.

(25) Prepared form Example 6ZI using methyl isocyanate.

(26) The formamide of Example 15A was prepared by the procedure Example6ZM, followed by reduction described for Example 15D.

(27) The amide bond is formed between an amino acid and aminobenzylcyclic urea using dicyclohexylcarbodiimide/catalytic1-hydroxybenzotriazole in N,N-dimethylformamide in the properproportions. When the desired product is to be a primary or secondaryamine, the N-terminus of the amino acid was first suitably protected,based on the compatability with later reactions (see T. W. Greene and P.G. M. Wuts, "Protecting Groups in Organic Synthesis", 2nd edition, Wiley(1991)) and then later removed.

(28) Cyclic urea XXIIc was alkylated with sodium hydride (2.5 equiv) andTHPO(CH₂)₅ Br (prepared in 2 steps from HO(CH₂)₅ OH)(4 equiv) in DMF togive the monoalkylated product. Where upon further treatment with sodiumhydride and a second bromo-alkylating agent provided an intermediatewhich was deprotected using methanolic HCl in dioxane to provide theproduct.

(29) Prepared by acidic deprotection of the monoalkyated intermediate.

(30) Prepared from intermediate (XXII) by treatment with phenyllithium,boron trifluoride and 1,2-epoxybutane, followed by acidic deprotection.

(31) Prepared from intermediate (XXII) by treatment with phenyllithium,boron trifluoride and 1,2-epoxyhexane, followed by acidic deprotection.

(32) Prepared by pyridinium chlorochromate oxidation of thecorresponding alcohol.

(33) Prepared from Example 15VQ using hydroxylamine hydrochloride.

(34) See preparation of Example 15VW using excess reagents.

(35) Prepared by selective monoalkylation of the dialkylated diol usingsodium hydride/methyl iodide.

(36) Prepared by substituting CH₃ CH(OTHP)(CH₂)₄ Br in the proceduredescribed for Example 15VE. Bromide is prepared from CH₃ CH(OH)(CH₂)₄ OHby the following sequence: (1) Ac₂ O; (2) THP, H⁺ ; (3) NaOH; (4) CBr₄,Ph₃ P.

(37) Prepared by substituting Ph₂ C═N(CH₂)₂ Br in the proceduredescribed for Example 15VE. Bromide is prepared from H₂ N(CH₂)₂ OH bythe following sequence: (1) Ph₂ CO; (2) CBr₄, Ph₃ P.

(38) See note 7, Table 2d.

(39) See note 3, Table 2d.

(40) See note 2, Table 2d.

(41) The intermediate was prepared by following Procedure 5 under thetitle of synthesis of monoalkyl cyclic urea. This was followed byalkylation with Bromo-m-tolunitrile. This intermediate (670 mg, 0.82mmol) was treated with potassium hydroxide (0.4 g, 7.13 mmol) inethylene glycol at 140° C. overnight. The solution was acidified withpre-cooled hydrochloric acid (1N) and extracted with ethyl acetate. Theorganic phase was concentrated to give 415 mg (61%) of MEM-protecteddiol. Procedure for hydrolysis of this product is covered underprocedure 5.

(42) The intermediate was prepared by following Procedure 5 under thetitle of synthesis of monoalkyl cyclic urea followed by alkylation withBromo-m-tolunitrile. This intermediate (210 mg, 0.26 mmol) was treatedwith DIBAL-H (0.19 mL, 1.5M in toluene, 0.286 mmol) at -78° C. undernitrogen, stirred at -78° C. for 1 hour and RT for 3 hours. The reactionwas quenched with cooled hydrochloric acid (1N) and worked up in theusual manner to give 180 mg (87%) of the MEM-protected product.Hydrolysis of this product is covered under procedure 5.

(43) N,N-dimethylformamide dimethyl acetal (2.1 ml, 15.9 mmol) was addedto a solution of ketone 9P (940 mg, 1.59 mmol) in ethanol. The mixturewas heated at reflux overnight, and the solvent was removed on a rotaryevaporator. The residue was purified on silica gel (15%methanol/chloroform) to provide the product (940 mg, 84%).

(44) The intermediate was prepared by following procedure 5 under thetitle of synthesis of monoalkyl cyclic urea. The monoalkylation productwas further alkylated with bromo-m-tolunitrile. This intermediate (185mg, 0.24 mmol) was treated with hydroxylamine.HCl (25 mg, 0.37 mmol),and triethylamine (0.05 ml, 0.37 mml) in refluxing ethanol for 16 h. Theresulting solution was partitioned between ethyl acetate/water. Theorganic layer was washed twice with water and concentrated to giveMEM-protected product which can be further hydrolyzed as described aboveto yield 90 mg (58%) product 9C.

(45) Guanidine carbonate (7.2 g, 40.23 mmol) was added to Ex 15AE inxylene. The mixture was heated at 130° C. until no starting material wasleft. The solution was partitioned between ethyl acetate/water and theorganic layer washed with water twice. The organic residue was purifiedon silica gel (10% methanol/ethyl acetate) to provide the pureproduct(347 mg, 37%).

(46) To a solution of MEM-protected formaldoxime 6C (0.5 g, 0.65 mol) inDMF was added 1/3 of N-chlorosuccinimide (173 mg, 1.3 mmol). The mixturewas stirred for 10 min followed by 2 min of heating at 40°-50° C. Afterstirring for another 10 min, the rest of NCS was added. The mixture wasstirred at room temperature for overnight. The solution was thenpartitioned between ethyl acetate/water. The organic layer was washedwith water and dried over MgSO₄. Treatment of the hydroximoyl chloridewith 3 equivalents of o-phenylenediamine in ethanol gave a singleproduct which can be further hydrolyzed to the product (126 mg, 43%).

(47) To a solution of aniline 3K (146 mg, 0.27 mmol) in methylenechloride, was added isonicotinoyl chloride hydrochloride (110 mg, 0.59mmol) followed by potassium carbonate (187 mg, 1.35 mmol) at 0° C. Themixture was stirred for 2 h and then slowly warmed up to roomtemperature overnight. The mixture was partitioned between ethylacetate/water. The organic layer was washed twice with water and driedover MgSO₄. The residue was purified on silica gel (5% methanol/ethylacetate) to gave the product (52 mg, 26%).

(48) The benzoyl chloride intermediate (0.51 g, 0.72 mmol) was preparedby following procedure (41) & (7) without removing MEM-protecting group.To the residue, 20 ml methylene chloride was added, followed by pyridine(0.11 ml, 1.44 mmol) and tert-butyl carbazate (190 mg, 1.44 mmol). Themixture was stirred at room temperature overnight. The mixture waswashed with water & dried over MgSO₄. The residue was purified on silicagel (10% ethyl acetate/methylene chloride). Following the hydrolysisprocedure described above, the product (182 mg) was isolated in 47%yield.

(49) To the MEM-protected hydrazide 10M (450 mg, 0.72 mmol) in dioxanewas added 165 mg (1.5 mmol) of CNBr followed by a solution of 125 mg(1.5 mmol) of sodium bicarbonate in 10 ml water. The resulting mixturewas stirred 2 h at room temperature. The solution was concentrated to1/2 volume in vacuo. The mixture was diluted with 10 ml of water and theresulting solid isolated by filtration and purified on silica gel (15%methanol/chloroform) to provide (38.4 mg, 8%).

(50) t-Butyl carbazate (264 mg, 2 mmol) was added to aldehyde 5V(450 mg,0.8 mmol) in ethanol. The mixture was stirred at room temperature for 2h and heated at reflux overnight. The residue was purified on silica gel(20% ethyl acetate/methylene chloride) to provide the product (179 mg,28%).

(51) To a solution of aniline 3K(160 mg, 0.3 mmol) in THF, chloroacetylisocyanate was added dropwise at 0° C. The mixture was stirred for 0.5 hand then slowly warmed up to room temperature overnight. The solutionwas partitioned between ethyl acetate/water. The organic phase waswashed with water and dried over MgSO₄. The residue was purified onsilica gel (5% methanol/chloroform) to gave 217 mg in 93% yield.

(53) To a solution of 333 mg (6.16 mmol) of anhydrous NaOCH₃ in 20 ml ofanhydrous methanol at 0° C. was added 855 mg (6.16 mmol) ofaminoguanidine carbonate followed by 2 ml methanol. The resultingmixture was treated dropwise with 500 mg (0.77 mmol) of ethyl ester 11Fwhich was made by following procedure (10) in 5 ml of methanol. Themixture was heated at reflux overnight, then poured into ice water,brought to PH 7 with 5% aqueous HCl, filtered, and purified on silicagel (10% methanol.chloroform) to give 20 mg (4%) product.

(54) A solution of MEM-protected cyclic urea wherein R²² and R²³ are(H2NC(═NOH))benzyl (210 mg, 0.26 mmol) and Et₃ N (0.18 ml, 1.3 mmol) wastreated dropwise with a solution of chloroacetyl chloride (0.046 ml,0.57 mmol) in CHCl₃. The mixture was stirred at room temperature for 2days and then evaporated, and the residue was redissolved in ethylacetate. The solution was washed with water, brine,dried over Na₂ SO₄.The residue was purified on silica gel (10% ethyl acetate/methylenechloride) to provide 140 mg (59%) intermediate. The intermediate wasdissolved in DMF and treated with excess dimethylamine gas. The mixturewas stirred overnight, then poured into ice water, and extracted withethyl acetate. The extracts were washed with water, dried over MgSO₄.Following the usual hydrolysis procedure, the product (15.6 mg) wasisolated in 10% yield.

Listed below are a representative list of data for compounds listed inTable 2d:

Example 12A: MS: 525 (M+1). NMR (CD₃ OD): δ 7.30-7.10 (m, 10H),3.96-3.88 (m, 2H), 3.58-3.42 (m, 4H), 3.37=3.28 (m, 4H), 3.17-3.10 (m,2H), 2.94-2.78 (m, 6H), 2.20-2.08 (m, 2H), 1.72-1.10 (br m, 14H).

Example 12B: MS: 516 (M+1, 100). NMR (CD₃ OD): δ 6.96-7.72 (br m, 15H),4.68 (d, 1H), 3.78-3.89 (m, 1H), 3.43-3.64 (m, 3H), 3.28-3.34 (m, 2H),3.10-3.19 (m, 1H), 2.81-3.02 (m, 6H), 2.12-2.26 (m, 1H), 1.10-1.84 (brm, 9H).

Example 12C: MS: 427 (M+1, 100). NMR (CDCl₃): δ 7.16-7.36 (m, 10H), 4.82(d, 1H), 3.88-3.98 (m, 2H), 3.37-3.69 (m, 8H), 3.04-3.19 (m, 3H),2.63-2.77 (m, 1H), 2.08-2.22 (m, 1H), 1.74-1.88 (m, 2H), 1.10-1.64 (brm, 6H).

Example 12D: MS: 527 (M+1, 1.00). NMR (CDCl₃): δ 7.17-7.38 (m, 10H),3.99 (s, 2H), 3.45-3.75 (m, 8H), 3.03-3.14 (m, 2H), 2.89-3.01 (m, 2H),2.60-2.68 (m, 2H), 2.12-2.24 (m, 2H), 1.12-1.62 (br m, 18H).

Example 12E: MS: 481 (M+1, 100). NMR (CDCl₃): δ 7.17-7.37 (m, 10H),3.94-4.13 (m, 2H), 3.61-3.75 (m, 2H), 3.43-3.61 (m, 4H), 3.05-3.20 (m,3H), 2.73-3.03 (m, 3H), 2.10-2.23 (m, 1H), 1.98-2.08 (m, 1H), 1.02-1.75(br m, 9H), 0.82-0.97 (m, 1H), 0.30-0.47 (m, 2H), 0.02-0.13 (m, 2H).

Example 12F: MS: 471 (M+1, 100). NMR (DMSO-d₆): δ 7.06-7.33 (m, 10H),5.25 (s, 2H), 4.34 (t, 2H), 3.71 (s, 2H), 3.44-3.58 (m, 2H), 3.20-3.42(m, 6H), 2.96-3.06 (m, 2H), 2.79-2.91 (m, 2H), 1.83-1.97 (m, 2H),1.08-1.42 (br m, 8H).

Example 12G: FABMS: 555 (M+1, 100). NMR (DMSO-d₆): δ 8.41 (s, 4H),7.06-7.33 (m, 10H), 3.71 (s, 2H), 3.33-3.50 (m, 5H), 3.00-3.09 (m, 2H),2.75-2.88 (m, 2H), 2.11-2.21 (m, 2H), 2.03-2.11 (m, 3H), 1.90-2.03 (m,2H), 1.02-1.54 (br m, 10 H).

Example 12H: MS: 583 (M+1, 100). NMR (CDCl₃): δ 7.12-7.35 (m, 10H), 3.98(s, 2H), 3.61 (s, 6H), 3.60-3.74 (m, 2H), 3.45-3.58 (m, 2H), 3.03-3.13(m, 2H), 2.84-3.03 (m, 4H), 2.07-2.28 (m, 6H), 1.08-1.81 (br m, 12H).

Example 12I: MS: 555 (M-CH₂ +1, 100). NMR (CDCl₃): δ 7.12-7.34 (m, 10H),3.98 (s, 2H), 3.62 (s, 3H), 3.45-3.76 (m, 6H), 3.04-3.13 (m, 2H),2.85-2.99 (m, 3H), 2.79 (s, 1H), 2.10-2.28 (m, 4H), 1.08-1.64 (br m,12H).

Example 12J: MS: 759 (M+1, 100), 633 (M-I+1, 33), 507 (M-2I+1, 17). NMR(CDCl₃): δ 7.00-7.64 (br m, 18H), 4.77 (d, 2H), 3.70 (s, 2H), 3.49-3.57(m, 2H), 2.99-3.12 (m, 4H), 2.81-2.93 (m, 2H), 2.29 (s, 2H).

Example 12K: MS: 583 (M+1, 100). NMR (CDCl₃): δ 7.15-7.35 (m, 10H), 3.98(s, 2H), 3.44-3.74 (m, 8H), 3.02-3.22 (m, 2H), 2.88-3.02 (m, 2H),2.02-2.20 (m, 2H), 0.94-1.92 (br m, 28H).

Example 12L: MS: 495 (M+1,100) NMR (CDCl₃): δ 7.31 (m,10H) 4.22 (m. 4H)3.76-4.05 (m. 6H) 3.60 (m, 2H) 3.03-3.37 (m, 6H) 1.89 (m, 2H) 0.95 (m,2H) 0.80 (m, 2H) 0.45 (m, 2H) 0.30 (m, 2H).

Example 12M: MS: 501 (M+1,100) NMR (CDCl₃): δ 7.05-7.38 (m, 15H) 4.84(dd,1H) 4.04 (m, 1H) 3.93 (m, 1H) 3.49-3.75 (m. 3H) 3.05 (m, 6H) 1.74(m, 2H) 0.70-0.98 (m, 2H) 0.40 (m, 1H) 0.28 (m, 1H).

Example 12N: MS: 411 (M+1, 100) NMR (CDCl₃): δ 7.25 (m, 10H) 4.72 (bs,1H) 3.95 (m, 5H) 3.53 (m. 2H) 3.11 (m. 6H) 2.94 (t, 1H) 2.76 (m. 1H)0.84 (m. 2H) 0.39 (m, 1H) 0.24 (m. 1H).

Example 12o: MS: 441 (M+1, 100). NMR (CDCl₃): δ 7.17-7.36 (m, 10H), 4.70(d, 1H), 3.90-4.01 (m, 2H), 3.53-3.68 (m, 4H), 3.37-3.45 (m, 1H),3.04-3.20 (m, 3H), 2.78-3.03 (m, 1H), 2.68-2.77 (m, 1H), 2.09-2.24 (m,1H), 1.10-1.95 (br m, 12H).

Example 12P: MS: 555 (M+1, 100). NMR (CDCl₃): δ 7.13-7.37 (m, 10H), 3.98(s, 2H), 3.44-3.77 (m, 10H), 3.03-3.14 (m, 2H), 2.80-3.01 (m, 4H),2.06-2.21 (m, 2H), 1.00-1.75 (br m, 20H).

Example 12Q: m. p. 185.7° C. FABMS: 655 (M+1, 100), 613 (M-HNCNH+1, 80).NMR (DMSO-d₆): δ 8.99 (br s, 8H), 6.87-7.62 (br m, 18H), 5.08-5.35 (m,2H), 4.44-4.62 (m, 2H), 3.41-3.61 (m, 4H), 2.96-3.18 (m, 4H), 2.64-2.81(m, 2H). Reference: K. Takagi, Chemistry Letters (1985), pp. 1307-1308.

Example 12R: m. p. 169.30° C. MS: 599 (M+1, 100). NMR (CDCl₃): δ6.90-7.40 (m, 18H), 4.88 (d, 2H), 3.63 (s, 2H), 3.49-3.58 (m, 2H),2.91-3.12 (m, 6H), 2.42 (s, 6H), 2.22 (s, 2H).

Example 12S: MS: 663 (M+1), 680 (M+NH₃ +1). NMR (CDCl₃): δ 6.93-7.83 (brm, 18H), 4.78 (d, 2H), 3.71 (s, 2H), 3.53-3.59 (m, 2H), 3.19 (d, 2H),3.00-3.14 (m, 4H), 2.98 (s, 6H), 2.75-2.83 (m, 2H).

Example 12T: MS: 415 (M+1). NMR (Acetone-d₆): δ 7.15-7.30 (m, 10H), 5.29(s, 1H), 4.41 (s, 1H), 4.25 (s, 1H), 3.81-4.05 (m, 3H), 3.63-3.78 (m,2H), 3.56-3.63 (m, 2H), 3.37-3.47 (m, 5H), 3.05-3.25 (m, 3H), 2.79-2.94(m, 1H), 2.20 (br s, 1H).

Example 12U: MS: 503 (M+1). NMR (Acetone-d₆): δ 7.15-7.28 (m, 10H), 4.29(s, 1H), 3.95-4.07 (m, 4H), 3.49-3.66 (m, 8H), 3.35-3.49 (m, 8H),3.14-3.22 (m, 2H), 3.02-3.09 (m, 2H), 2.08-2.21 (m, 3H).

Example 12V: MS: 569 (M+1). NMR (CDCl₃): δ 7.14-7.34 (m, 10H), 3.90-4.03(m, 4H), 3.42-3.74 (m, 8H), 3.03-3.14 (m, 2H), 2.86-3.01 (m, 2H),2.68-2.86 (m, 2H), 2.05-2.23 (m, 2H), 2.01 (s, 3H), 0.98-1.75 (br m, 15H).

Example 12W: MS: 641 (M+1), 584 (M-CONHCH₂ +1), 527 (M-2CONHCH₂ +1). NMR(CDCl₃): δ 7.10-7.35 (m, 10H), 4.77 (br s, 2H), 3.89-4.12 (m, 6H),3.60-3.80 (m, 2H), 3.35-3.47 (m, 2H), 3.04-3.16 (m, 2H), 2.87-3.01 (m,2H), 2.78 (d, 6H), 2.01-2.16 (m, 2H), 0.98-1.80 (br m, 18H).

Example 12X: MS: 626 (M+1), 569 (M-CONHCH₂ +1). NMR (CDCl₃): δ 7.09-7.35(m, 10H), 4.79 (br s, 1H), 3.82-4.14 (m, 6H), 3.38-3.81 (m, 4H),3.01-3.22 (m, 2H), 2.83-3.01 (m, 2H), 2.79 (d, 3H), 2.04-2.20 (m, 2H),2.01 (s, 3H), 0.96-1.84 (br m, 18 H).

Example 12Y: MS: 584 (M+1), 527 (M-CONHCH₂ +1). NMR (CDCl₃): δ 7.11-7.41(m, 10H), 4.81 (br s, 1H), 3.87-4.10 (m, 4H), 3.41-3.76 (m, 6H),3.02-3.16 (m, 2H), 2.81-3.02 (m, 2H), 2.78 (d, 3H), 2.00-2.21 (m, 2H),1.79 (br s, 1H), 0.95-1.63 (br m, 18H).

Example 12Z: MS: 425 (M+1, 100).

Example 13A: MS: 439 (M+1, 100).

Example 13B: MS: 481 (M+1, 100).

Example 13C: MS: 635 (M+1, 100) 652 (M+NH₄).

Example 13D: MS: 491 (M+1,100); NMR (CDCl₃): δ 7.24 (m,10H), 5.68(m,2H), 4.90 (m,4H), 3.98 (s,2H), 3.66 (m,2H), 3.50 (m,2H), 3.04 (m,4H),2.19 (m,2H), 1.95 (m,4H), 1.22 (m,8H).

Example 13E: MS: 523 (M+1,100); NMR (CDCl₃): δ 7.19 (m,10H), 3.98(s,2H), 3.66 (m,2H), 3.53 (m,2H), 3.23 (s,2H), 3.14-2.66 (m,8H), 2.40(m,2H), 2.21 (m,2H), 1.55-1.23 (m,12H).

Example 13F: MS: 811 (M+1,100); NMR (CDCl₃): δ 7.22 (m,10H), 4.00(m,4H), 3.77 (dd,2H), 3.56 (m,6H), 3.13 (m,4H), 2.93 (m,2H), 2.23(m,2H), 2.00 (m,2H), 1.65 (m,2H), 1.50-1.23 (m,8H).

Example 13G: MS: 685 (M+1,100); NMR (CDCl₃): δ 7.22 (m,10H), 4.01(m,2H), 3.72-3.26 (m,12H), 3.14 (d,2H),2.96-2.70 (m,6H), 2.26 (m,2H),1.43-1.18 (m,8H).

Example 13H: MS: 499 (M+1,100); NMR (CDCl₃): δ 7.23 (m,10H), 3.99(s,2H), 3.54 (m,8H), 3.12 (m,2H), 2.94 (m,4H), 2.22 (m,2H), 1.47-1.20(m,12H).

Example 13I: MS: 559 (M+1,100); NMR (CDCl₃ /CD₃ OD): δ 7.02 (m,10H),3.79 (s,2H), 3.69 (s,2H), 3.28 (m,6H), 3.13 (m,4H), 2.86 (m,2H), 2.67(m,2H), 1.95 (m,2H), 1.09-0.90 (m,12H).

Example 13J: MS: 435 (M+1,100); NMR (CDCl₃): δ 7.26 (m,10H), 4.15(m,1H), 3.86 (m,1H), 3.76 (m,1H), 3.64 (m,1H), 3.53 (m,2H), 3.23-2.97(m,4H), 2.78 (m,2H), 2.16 (d,1H), 1.92 (m,1H), 1.18 (m,1H), 0.88 (m,1H),0.58 (m,2H), 0.46 (m,2H), 0.29 (d,1H), 0.07 (d,1H).

Example 13K: MS: 407 (M+1,100); NMR (CDCl₃): δ 7.23 (m,10H), 6.05(m,1H), 5.67 (m,1H), 5.25 (m,2H), 5.05 (dd,2H), 4.17 (m,2H), 3.96(m,1H), 3.83 (m,1H), 3.65 (m,1H), 3.55 (m,1H), 3.12-2.79 (m,5H), 2.59(br s,1H), 2.35 (d,1H).

Example 13L: MS: 507 (M+1,100); NMR (CDCl₃): δ 7.28 (m,18H), 6.91(d,2H), 4.10 (d,2H), 3.92 (d,1H), 3.58 (m,4H), 3.18-2.63 (m,5H).

Example 13M: MS: 567 (M+1,100); NMR (CDCl₃): δ 7.46-6.95 (m,18H), 4.90(dd,2H), 4.67 (br d,4H), 3.84 (d,1H), 3.53 (m,4H), 3.09-2.75 (m,5H),2.44 (d,1H).

Example 13N: MS: 407 (M+1,100); NMR (CDCl₃): δ 7.24 (m,10H), 5.55(m,2H), 5.14 (m,4H), 4.07 (dd,2H), 3.74 (m,2H), 3.27 (m,2H), 3.12-2.84(m,6H), 2.09 (s,2H).

Example 13o: MS: 435 (M+1,100); NMR (CDCl₃): δ 7.26 (m,10H), 3.85(s,2H), 3.41 (m,4H), 3.01 (ddd,4H), 2.28 (dd,2H),2.19 (s,2H), 0.93(m,2H), 0.50 (m,2H), 0.16 (m,2H).

Example 13P: MS:327 (M+1,100); NMR (CDCl₃): δ 7.28 (m,10H), 4.25 (m,2H),3.35 (m,6H), 2.81 (m,2H), 2.65 (m,2H).

Example 13Q: MS: 507 (M+1,100); NMR (CDCl₃): δ 7.24 (m,20H), 4.74(d,2H), 3.55 (m,4H), 3.20 (m,2H), 2.96 (m,2H), 2.77 (m,2H).

Example 13R: MS: 439 (M+1,100); NMR (CDCl₃): δ 7.26 (m,10H), 3.75(s,2H), 3.62 (m,2H), 3.20 (m,2H), 3.08 (m,2H), 2.84 (m,2H), 2.38 (m,2H),1.38-1.23 (m,8H), 0.90 (m,6H).

Example 13S: MS: 567 (M+1,100); NMR (CDCl₃): δ 7.34-7.07 (m,18H), 4.68(m,6H), 3.57 (m,4H), 3.17 (m,2H), 2.96 (m,2H), 2.79 (m,2H).

Example 13T: MS: 617(M+H,100%); NMR (CDCl₃,300 MHz): δ 7.3(m,10H),6.7(m,4H), 6.35(m,2H), 4.75(d,2H), 3.5(s,4H), 3.3(m,4H), 3.0(m,6H),2.7(m,4H), 1.9(m,4H).

Example 13U: m.p. 264°-266° C.; MS: 609(M+H,100%); NMR (CDCl₃,300 MHz):δ 8.6(d,2H), 7.95(d,2H), 7.8(d,2H), 7.6(d,2H), 7.3(m,14H), 5.1(d,2H),3.7(m,4H), 3.2(m,6H).

Example 13V: MS: 521(M+H,100%); NMR (CDCl₃,300 MHz): δ 8.8(s,2H),7.2(m,12H), 4.15(s,2H), 3.8(t,2H), 3.6(m,4H), 2.9(m,4H).

Example 13W: m.p. 182°-184° C.; MS: 687(M+H,100%); NMR (CDCl₃,300 MHz):δ 7.2(m,10H), 6.95(d,2H), 6.2(d,2H), 4.9(d,2H), 4.15(d,2H), 3.9(bs,2H),3.7(d,2H), 3.0(m,6H), 1.45(s,18H)

Example 13X: MS: 547(M+H,100%); NMR (CDCl₃,300 MHz): δ 7.2(m,10H),6.2(d,2H), 6.0(d,2H), 4.8(d,2H), 4.5(bs,2H), 3.8(s, 2H), 3.5(d,2H),3.1(m,6H).

Example 13Y: MS: 507 (M+1, 100%); NMR (CDCl₃,300 MHz): δ 7.0-7.4 (m,20H), 4.7-4.8 (d, 2H), 4.5 (m, 2H), 3.45 (m, 4H), 3.1 (m, 4H), 2.9 (m,2H).

Example 13Z: MS: 577((M+H)⁺, 100%); 594((M+NH₄)⁺, 80%). NMR (CDCl₃): δ8.08(s 1H), 7.48(dd, 1H, J=8.4, 1.9 Hz), 7.25-7.38(m, 3H); 7.19(d, 1H,J=8.4 Hz), 7.00-7.03(m, 2H), 3.96(ABq, 2H), 3.73(d, 1H, J=1.1 Hz),3.50(dd, 1H, J=11.4, 1.1 Hz), 3.23(br.s., 1H), 2.98(ABx, 2H).

Example 14A: NMR (CDCl₃): δ 8.27(dd, 1H, J=4.9, 2.0 Hz), 7.66(dd, 1H,J=7.5, 2.0 Hz), 7.14-7.27(m, 4H), 6.68(dd, 2H, J=7.5, 3.6 Hz), 4.16(d,1H, J=0.8 Hz), 3.90(ABq, 2H), 3.72(dd, 1H, J=11.3, 1.1 Hz), 3.14(br.s.,1H), 2.87(ABx, 2H).

Example 14B: MS: 685((M+H)⁺, 100%). NMR (CDCl₃): δ 8.34(dd, 1H, J=4.8,1.9 Hz), 7.16-7.37(m, 4H), 6.93(dd, 1H, J=7.6, 4.8 Hz), 6.87(dd, 2H,J=7.5, 1.7 Hz), 4.14(s, 1H), 3.90(ABq, 2H), 3.68(td, 1H, J=6.3, 0.7 Hz),2.99(d, 2H, J=6.3 Hz), 2.43(br.s., 1H).

Example 14C: MS: 541((M+H)⁺, 100%). NMR (CD₃ OD): δ 7.53(dd, 1H, J=9.5,2.6 Hz), 7.15-7.26(m, 3H), 7.06(d, 1H, J=2.6 Hz), 6.96-6.99(m, 2H),6.42(d, 1H, J=9.5 Hz), 3.80(s, 1H), 3.71(ABq, 2H), 3.62(dd, 1H, J=11.7,0.7 Hz), 2.92(ABx, 2H).

Example 14D: MS: 458(M+H⁺, 100%).

Example 14E: MS: 543(M+H⁺, 100%) NMR (CDCl₃): δ 7.4-7.1(m, 5H), 4.42(d,J=17.5 Hz, 1H), 4.10(s, 1H), 3.83(d, J=10.6 Hz), 3.2-3.0(m, 2H), 2.82(d,J=17.6 Hz, 1H), 2.36(s, 1H), 2.14(m, 2H), 1.5-1.2(m, 6H), 0.85(t, J=7.0Hz, 3H).

Example 14F: MS: 739.5(M+H⁺) NMR (CDCl₃): δ 7.4-7.0(m, 15H), 3.90(s,1H), 3.3-3.1(m, 2H), 3.04(m, 2H), 2.43(dd, J=14.7, 5.7 Hz, 1H), 2.17(s,1H), 1.824(m, 1H), 1.26(t, J=6.0 Hz, 1H), 1.02(dd, J=9.0, 5.1 Hz, 1H)

Example 14G: MS: 479(M+H⁺, 100%) NMR (CDCl₃): δ 7.24(bs, 5H),7.15-6.9(m, 3H), 6.72(d, J=7.5 Hz, 2H), 4.15(s, 1H), 4.06(d, J=10.5 Hz,1H), 3.5-3.2(m, 2H), 2.98(s, 1H).

Example 14H: MS: 587(M+H⁺, 100%) NMR (CDCl₃): δ 7.4-6.9(m, 10H), 3.92(s,1H), 3.8-3.6(m, 2H), 3.03(m, 2H), 2.50(bs, 1H), 2.19(dd, J=14.3, 7.0 Hz,1H), 1.57(m, 1H), 1.0-0.7(m, 2H).

Example 14I: MS: 457(M+H⁺, 100%), 474(M+NH₄ ⁺, 15%) NMR (CDCl₃): δ7.4-6.9(m, 15H), 4.69(d, J=6.2 Hz, 1H), 3.95(m, 2H), 3.77(m, 2H),3.37(m, 1H), 3.25-3.0(m, 3H), 2.15(b, 1H), 1.61(m, 2H), 1.24(m, 1H),1.0-0.7(m, 2H).

Example 14J: NMR (CDCl₃): δ 7.42(d, 2H, J=7.3 Hz), 7.22-7.38(m, 6H),7.11(d, 2H, J=6.6 Hz), 6.54(s, 1H), 6.35(s, 1H), 5.31(s, 2H), 3.84(ABq,2H), 3.72(s, 1H), 3.49(d, 1H, J=10.4 Hz), 2.90-3.01(m, 2H), 2.39(s, 3H).

Example 14K: NMR ((CD₃)₂ SO): δ 7.00-7.33(m, 7H), 3.61(s, 1H), 3.55(ABq,2H), 3.45(d, 1H, J=11.0 Hz), 2.95(AB_(x), 2H), 2.09(s, 3H,).

Example 15VA: NMR (CDCl₃): δ 7.19-7.40 (m, 10H) 4.66 (d, 1H) 3.99-4.12(m, 2H) 3.59-3.69 (m, 2H) 3.37-3.49 (m, 2H) 3.10-3.21 (m, 2H) 2.25-2.38(m, 3H) 1.90-2.00 (m, 2H) 0.85-0.92 (m, 8H).

Example 15VB: NMR (CD₃ OD): δ 7.50-7.70 (m, 1H) 7.10-7.35 (m, 9H) 3.95(m, 2H) 3.53-3.70 (m, 2H) 3.40-3.50 (m, 2H) 3.00-3.20 (m, 3H) 2.75 (t,1H) 2.30 (m, 1H) 1.60-2.10 (m, 7H) 1.28 (m, 2H) 0.81-1.10 (m, 2H).

Example 15VC: NMR (CDCl₃): δ 7.15-7.40 (m, 10H) 4.70 (d, 1H) 4.05 (m,2H) 3.50-3.70 (m, 3H) 3.57 (m, 1H) 3.20 (m, 1H) 3.07 (s, 3H) 3.05 (s,3H) 2.75 (t, 1H) 2.59 (s, 2H) 2.93 (m, 2H) 1.40-1.55 (m, 5H) 1.17-1.32(m, 2H) 1.00-1.15 (m, 2H).

Example 15VD: NMR (CDCl₃): δ 7.05-7.30 (m, 10H), 5.55 (br s, 2H), 3.93(s, 2H), 3.66-3.80 (m, 4H), 3.53 (d, 2H), 3.09 (d, 2H), 2.85-2.92 (m,2H), 2.81 (d, 6H), 1.98-2.26 (m, 6H), 0.96-1.52 (br m, 12H).

Example 15VE: NMR (CDCl₃): δ 7.17-7.34 (m, 10H), 3.99 (s, 2H), 3.55-3.73(m, 4H), 3.43-3.53 (m, 4H), 3.05-3.13 (m, 2H), 2.90-3.00 (m, 2H), 2.58(br d, 2H), 2.15-2.28 (m, 2H), 1.12-1.80 (br m, 17H).

Example 15VF: NMR (CDCl₃): δ 7.17-7.34 (m, 10H), 4.57 (br s, 1H), 4.08(t, 2H), 3.99 (s, 2H), 3.60-3.72 (m, 2H), 3.59 (t, 2H), 3.46-3.54 (m,2H), 3.05-3.13 (m, 2H), 2.89-3.00 (m, 2H), 2.78 (d, 3H), 2.70 (br s,2H), 2.14-2.24 (m, 2H), 1.12-1.80 (br m, 17H).

Example 15VG: NMR (CDCl₃): δ 7.10-7.37 (m, 10H), 4.80 (d, 1H), 3.92 (s,2H), 3.20-3.70 (br m, 6H), 3.00-3.19 (m, 4H), 3.61-3.77 (m, 1H), 2.21(br s, 1H), 1.10-1.50 (br m, 7H).

Example 15VH: NMR (CDCl₃): δ 7.64-7.84 (m, 3H), 7.05-7.57 (m, 14H), 4.96(d, 1H), 3.92 (m, 1H), 3.38-3.80 (m, 6H), 3.21 (d, 1H), 2.99-3.18 (m,3H), 2.75-2.98 (m, 2H), 2.43 (br s, 1H), 2.20-2.35 (m, 1H), 1.10-1.88(br m, 7H).

Example 15VI: NMR (CDCl₃): δ 7.04-7.40 (m, 15H), 4.80 (d, 1H), 3.94 (m,1H), 3.42-3.80 (m, 7H), 2.83-3.17 (m, 6H), 2.64 (br s, 1H), 2.19-2.31(m, 1H), 1.16-1.50 (br m, 6H).

Example 15VJ: NMR (CDCl₃): δ 7.11-7.35 (m, 10H), 3.99 (s, 2H), 3.43-3.69(m, 6H), 3.10 (m, 2H), 2.95 (m, 3H), 2.80 (s, 1H), 2.38 (t, 2H), 2.20(m, 2H), 2.02 (s, 3H), 1.18-1.56 (br m, 13H).

Example 15VK: NMR (CDCl₃): δ 7.05-7.40 (m, 14H), 4.79 (d, 1H), 4.58-4.70(m, 2H), 4.50 (d, 1H), 3.91 (m, 1H), 3.40-3.75 (m, 6H), 2.98-3.14 (m,4H), 2.81-2.95 (m, 2H), 2.72 (s, 1H), 2.25 (m, 1H), 2.07 (br s, 1H),1.16-1.50 (br m, 6H).

Example 15VL: NMR (CDCl₃): δ 7.18-7.36 (10H, m) 4.53 (1H,s) 3.95 (2H,s)3.79 (1H,m) 3.51 (1H,m) 3.33 (2H,m) 3.13 (6H,m) 2.72 (1H,t) 2.60 (1H,s)1.33 (2H,m) 0.84 (3H,t).

Example 15VM: NMR (CDCl₃): δ 7.20-7.34 (10H,m) 4.57 (1H,s) 3.94 (2H,s)3.79 (1H,m) 3.52 (1H,m) 3.38 (1H,m) 3.33 (1H,d) 3.13 (5H,m) 2.94(2H,.bs) 2.72 (1H,t) 1.26 (6H,m) 0.86 (3H,t).

Example 15VQ: NMR (CDCl₃): δ 7.14-7.35 (10H, m) 4.63 (2H,d) 4.41 (2H,s)3.49 (2H,d) 3.34 (2H,m) 3.14 (2H,m) 2.85 (2H,d) 2.45 (2H,s) 2.10-2.32(4H,m) 0.99 (6H,t).

Example 15VP: NMR(CDCl3): δ 8.81 (2H,s) 7.23 (10H, m) 4.80 (2H,d) 4.14(4H, m) 3.68 (2H, m) 3.14 (2H, m) 2.60 (2H.d) 2.44 (2H,m) 2.03 (2H,m)0.98 (6H,t).

Example 15VQ: NMR (CDCl₃): δ 7.64-7.82 (m, 3H), 7.07-7.53 (m, 14H), 4.96(d, 1H), 3.88-3.96 (m, 1H), 3.44-3.80 (m, 7H), 3.21 (d, 1H), 2.99-3.16(m, 3H), 2.84-2.98 (m, 1H), 2.70 (s, 1H), 2.19-2.33 (m, 2H), 1.08-1.56(br m, 8H).

Example 15VR: NMR (Acetone-d₆): δ 8.38 (s, 1H), 7.02-7.40 (m, 11H), 6.70(m, 2H), 6.52 (d, 1H), 4.73 (d, 1H), 4.34 (s, 2H), 3.84-3.96 (m, 1H),3.38-3.76 (br m, 7H), 2.80-3.21 (br m, 5H), 2.07-2.19 (m, 1H), 1.16-1.52(br m, 6H).

Example 15VS: NMR (CDCl₃): δ 7.15-7.33 (m, 10H), 4.00 (s, 2H), 3.44-3.69(m, 5H), 3.10 (d, 2H), 2.88-2.98 (m, 3H), 2.85 (s, 3H), 2.56-2.76 (m,2H), 2.17-2.35 (m, 2H), 1.18-1.80 (m, 15H).

Example 15VU: NMR (CDCl₃): δ 7.10-7.36 (m, 10H), 4.04 (m, 2H), 3.39-3.79(br m, 7H), 2.78-3.22 (br m, 6H), 2.17-2.29 (m, 1H), 2.03 (m, 1H),1.15-1.52 (br m, 6H), 0.91 (m, 1H), 0.41 (m, 2H), 0.06 (m, 2H).

Example 15VV: NMR (CDCl₃): δ 7.15-7.33 (m, 10H), 3.99 (s, 2H), 3.65 (m,2H), 3.49 (d, 2H), 3.25 (s, 6H), 3.21-3.33 (m, 4H), 3.04-3.14 (m, 2H),2.89-3.00 (m, 2H), 2.63 (s, 2H), 2.18 (m, 2H), 1.72 (br s, 2H),1.15-1.52 (br m, 10H).

Example 15VW: NMR (CDCl₃): δ 7.13-7.33 (m, 10H), 3.99 (s, 2H), 3.45-3.71(br m, 6H), 3.24 (s, 3H), 3.20-3.33 (m, 3H), 3.10 (d, 3H), 2.89-3.00 (m,2H), 2.10-2.28 (m, 2H), 1.85 (br d, 2H), 1.15-1.53 (br m, 11H).

Example 15VX: NMR (CDCl₃): δ 7.13-7.57 (br m, 11H), 6.98 (d, 3H), 4.68(d, 1H), 3.98 (m, 1H), 3.74-3.83 (m, 2H), 3.46-3.69 (m, 3H), 3.22 (d,1H), 3.01-3.18 (m, 3H), 2.81-2.93 (m, 3H), 2.66 (br d, 2H), 2.23 (m,1H), 1.18-1.56 (br m, 6H).

Example 15VY: NMR (CDCl₃): δ 7.91 (m, 1H), 7.83 (s, 1H), 7.17-7.39 (m,10H), 7.09 (d, 2H), 4.84 (d, 1H), 4.31 (q, 2H), 3.95 (dd, 1H), 3.62-3.72(m, 2H), 3.48-3.60 (m, 4H), 2.86-3.16 (br m, 5H), 2.57 (br s, 1H), 2.39(br s, 1H), 2.29 (m, 1H), 1.05-1.52 (br m, 10H).

Example 15VZ: NMR (CDCl₃): δ 7.17-7.32 (10H,m) 3.99 (2H,s) 3.68 (4H,m)3.50 (2H,d) 3.09 (2H,dd) 2.94 (2H,t) 2.62 (2H,s) 2.23 (2H,m) 1.33(14H,m) 1.12 (6H,d).

Example 15WB: NMR (CDCl₃): δ 7.13-7.33 (m, 10H), 4.02 (s, 2H), 3.61 (m,2H), 3.50 (d, 2H), 3.10 (dd, 2H), 2.85-2.97 (m, 2H), 2.82 (s, 2H), 2.33(t, 4H), 2.18 (m, 2H), 2.06 (s, 6H), 1.18-1.50 (br m, 8H).

Example 15WC: NMR (DMSO-d₆): δ 10.17, 10.09 (2 singlets, 2H-3:1 mixtureof isomers), 7.08-7.32 (m, 10H), 5.21 (s, 2H), 3.70 (s, 2H), 3.48 (m,2H), 3.38 (d, 2H), 3.03 (d, 2H), 2.81 (m, 2H), 1.91-2.19 (br m, 6H),1.61-1.71 (m, 6H), 1.15-1.39 (m, 8H).

Example 15WD: NMR (DMSO-d₆): δ 6.91-7.40 (br m, 14H), 5.01-5.22 (m, 1H),4.61 (m, 1H), 4.42-4.50 (m, 1H), 3.66 (m, 1H), 3.12-3.54 (br m, 7H),3.06 (d, 1H), 2.75-2.99 (m, 4H), 2.32-2.57 (m, 4H), 1.94-2.07 (m, 1H),1.05-1.38 (br m, 8H).

Example 15WE: NMR (CDCl₃): δ 7.18-7.38 (m, 10H), 7.33 (s, 1H), 7.06 (m,3H), 4.80 (d, 1H), 4.60 (d, 2H), 3.94 (m, 1H), 3.46-3.75 (m, 7H),2.80-3.15 (m, 7H), 2.23-2.42 (m, 2H), 1.18-1.50 (br m, 6H).

15BC; MS (DCI): 514 (M+H⁺, 100%). ¹ H NMR (CD₃ OD, 300 MHz) δ 0.1 (m,2H), 0.4 (m, 2H), 0.8 (m, 1H), 1.9 (m, 1H), 3.0 (m, 4H), 3.3 (d, 1H),3.4 (m, 2H), 3.6 (m, 1H), 3.75 (m,1H), 4.0 (m, 1H), 4.4 (d,1H), 6.8-7.4(m,13H).

15AA ¹ H NMR (CD₃ OD, 300 MHz) δ 3.00(m, 6H), 3.6 (m, 4H), 4.4 (s, 4H),4.7 (d, 2H), 6.9-7.5 (m, 18H).

15AM MS (DCI): 661 (M+H,100%). ¹ H NMR (CD₃ OD, 300 MHz) δ 1.2 (t, 3H),3.0 (m, 6H), 3.6 (m, 4H), 4.3 (q, 2H), 4.8 (d,2H), 7.0-7.4 (m, 18),7.8-8.0 (m, 3H).

15AQ: MS (DCI): 548 (M+H, 100%). ¹ H MNR (CD₃ OD, 300 MHz) δ 3.0 (m,6H), 3.6 (m, 4H), 4.8 (m, 2H), 6.8-7.8 (m, 18H).

15AR: MS (DCI): 533 (M+H, 100%). ¹ H NMR (CD₃ OD, 300 MHz) δ 3.0 (m,6H), 3.7 (m, 4H), 4.7 (d, 2H), 4.8 (d, 1H), 7.0-8.4 (m, 18H).

15AO: ¹ H NMR (CD₃ OD, 300 MHz) δ 2.4 (s, 12H), 3.0 (m, 6H), 3.6 (s,4H),3.9 (s, 4H), 4.8 (d, J=15 Hz,2H), 7.05-7.50(m, 14H) 7.96(d, J=7.5 Hz,2H), 8.0(s, 2H).

The structures of the Examples below are shown in Table 2e.

Ketal formation: Preparation of Triacetonide (XXVIa):

Lithium borohydride (1.2 gr, 56.2 mmol) was added in four portions to asuspension of L-mannonic-g-lactone (5 gr, 28.1 mmol) in methanol (250mL) at 0° C. over 10 min. Ice bath was removed and reaction stirred atroom temperature for 30 min. Reaction was quenched at 0° C. with 2N HCl.Solvent was evaporated and residue taken up in acetone (75 mL) to which2,2-dimethoxypropane (20 mL, 168.6 mmol) and camphorsulphonic acid (20gr, 84.3 mmol) were added in four portions. Reaction becomes clear for afew minutes and then a precipitate forms. Reaction stirred at roomtemperature for 14 h. Solvent volume then reduced by 2/3 at reducedpressure and then poured into EtOAc, washed with saturated NaHCO₃, dried(MgSO₄) and concentrated. Solid residue taken up in hexane and filteredthru a pad of silica gel. Filtrate concentrated to give triacetonide(XXVIa) as a yellowish solid (7.1 gr, 80%). m.p. 72°-74° C.; MS: 303(M+H,100%); NMR (CDCl₃,300 MHz): δ 4.25 (m, 2H), 4.15 (m, 2H), 4.05 (m,4H), 1.5 (s, 6H), 1.45 (s, 6H), 1.4 (s, 6H).

Selective Acetonide Deprotection: Preparation of Tetraol (XXVIb):

Compound (XXVIa) (14 gr) in 70% AcOH (200 mL) was stirred at 45° C. for2 h. Solvent removed at reduced pressure with a bath temperature of 45°C. Residue recrystalized from ether. Mother liquors concentrated andchromatographed (silica, 10% methanol in methylene chloride) to give thedesired product as a white solid (8.2 gr, 80%). m.p. 91°-93° C.; a!_(D)=-26.40 (c=3, H2O); MS: 240 (M+NH₄,100%); NMR (CDCl₃,300 MHz): δ 3.95(m, 6H), 3.75 (m, 4H), 2.5 (bs, 2H), 1.4 (s,6H).

Epoxide Formation: Preparation of Diepoxide (XXVIc):

A solution of Compound (XXVIb) (1 g, 4.5 mmol) in pyridine (5 mL) wascooled to -20° C. and treated with p-toluenesulfonyl chloride (1.89 g,10 mmol). Stirring continued at -20° C. for 20 min, 0° C. for 20 min,and 23° C. for 20 min. The reaction was then diluted with methylenechloride and washed with 2N HCl and NaHCO₃. The organic extract wasdried over MgSO₄ and concentrated. The crude product was then taken upin methanol (14 mL) and cooled to 0° C. Next, K₂ CO₃ (3.11 g, 22 mmol)was added and the reaction stirred at room temperature for 30 min. Themethanol was then stripped off (do not evaporate to dryness, epoxide isvolatile) and the crude was washed with water, extracted with ether,dried over MgSO₄, filtered, and concentrated. The compound was purifiedon SiO₂ and eluted with 30-60% ether/petroleum ether to afford thediepoxide (0.63 g, 75%) as an oil. NMR (CDCl₃,300 MHz): δ 3.81 (m, 2H),3.10 (m, 2H), 2.80 (t, 2H), 2.68 (m, 2H), 1.40 (s, 6H, CH₃).

Opening of Epoxide: Prepepartion of Diol (XXVId):

To a suspension of cuprous bromide-dimethyl sulfide complex (1.8 g, 8.7mmol) in anhydrous THF (5 mL) at -20° C. was added 8.5 mlbenzylmagnesium chloride (2M in THF, 17 mmol). Reaction stirred at -20°C. for 30 min and at 0° C. for 1 h. Next, Compound (XXVIc) (0.54 g, 3mmol) in THF (5 mL) was added, and the reaction stirred at 0° C. for 1h. The excess reagent was quenched with saturated NH₄ Cl solution andallowed to warm to room temperature. The contents were then washed withwater and brine, extracted with ether, dried over MgSO₄, filtered, andconcentrated. Crude material was then purified by flash chromatography(30-60% ether/petroleum ether) to yield 0.84 g (78%) of an oil. MS: 371(M+H,66%); NMR (CDCl₃,300 MHz): δ 7.2-7.4 (m, 10H), 4.65 (s, 2H),3.6-3.8 (m, 4H), 2.6-3.0 (m, 4H), 1.8-2.2 (m, 4H), 1.4 (s, 6H).

Hydroxyl Displacement: Preparation of Diazide (XXVIe):

To a solution of Compound (XXVId) (0.48 g, 1.3 mmol) and triphenylphosphine (1.0 g, 3.9 mmol) in THF (5 mL) at 0° C. was addeddiethylazodicarboxylate (0.61 mL, 3.9 mmol) and dipheylphosphorylazide(0.84 mL, 3.9 mmol). Contents were allowed to warm to room temperaturein the ice bath for 1 h. The excess reagents were quenched by theaddition of methanol (0.2 mL, 5 mmol) at 0° C. The mixture was thenstirred at room temperature for 30 min and then concentrated to a smallvolume. Crude was then purified on SiO₂ using 1:40 ethyl acetate/hexanegiving 0.245 g (45%) of an oil. MS: 438 (M+NH₄,8%); NMR (CDCl₃,300 MHz):δ 7.2-7.4 (m, 10H), 4.18 (s, 2H), 2.7-3.0 (m, 6H), 2.0-2.3 (m, 4H), 1.58(s, 6H).

Reduction of Diazide (XXVIe):

To Compound (XXVIe) (0.245 g, 0.58 mmol) in ethanol (6 mL) under N₂ wasadded 10% Pd/C (73.5 mg, 30%/weight) Reaction stirred under H₂atmosphere at room temperature overnite. Crude was then filtered throughcelite and concentrated. 0.21 g (98%) of the diamine was collected as anoil and taken onto next step without further purification. MS:369(M+H,100%); NMR (CDCl₃,300 MHz): δ 7.05-7.3 (m, 10H), 3.9 (bs, 2H),3.05 (bs. 4H), 2.8 (m, 2H), 2.6 (m, 4H), 1.7 (bs, 4H), 1.35 (s, 6H).

Cyclization of the Diamine: Formation of Cyclic Urea (XXVIf):

The diamine (0.21 g, 0.57 mmol) was dissolved in methylene chloride (50mL) and carbonyldiimidazole (0.102 g, 0.63 mmol) was added and thereaction stirred at 23° C. overnite. The solution was then concentratedand purified on SiO₂ using 75% ethyl acetate/hexane as elutent whichgave 85 mg (38%) of (XXVIf) as a foam. MS: 395 (M+H,100%); NMR(CDCl₃,300 MHz): δ 7.0-7.2 (m, 10H), 3.6-4.0 (m, 4H), 3.6-2.7 (m, 4H),1.8-1.9 (m, 4H), 1.3 (s, 6H).

Alkylation of the Cyclic Urea (XXVIf):

To Compound (XXVIf) (85 mg, 0.22 mmol) in dry DMF (3 mL) was added 60%NaH (0.07 g, 1.7 mmol). The solution was stirred for 5 min at roomtemperature. Next, benzyl bromide (0.1 mL, 0.86 mmol) was added and thereaction stirred at 23° C. overnite. Reaction was then quenched withmethanol (several drops), washed with H₂ O, extracted with ether, dried(MgSO₄), and concentrated. Crude was then purified on silica gel using1:1 hexane/ethyl acetate affording 0.03 g (25%) of the bis-alkylatedurea as a foam. MS: 575 (M+H,100%); NMR (CDCl₃, 300 MHz): δ 7.1-7.4 (m,20H), 5.1 (d, 2H), 4.0 (d, 2H), 3.75 (bs, 2H), 3.6 (m, 2H), 2.7 (m, 2H),2.6 (m, 2H), 1.9-2.0 (m, 4H), 1.25 (s, 6H).

Deprotection of Acetonide: Preparation of Example 16A:

To above prepared bis-alkylated cyclic urea (0.03 g, 0.05 mmol) in THF(2 mL) at room temperature was added several drops of concentrated HCl.Reaction stirred at room temperature for 2 h. Reaction was then washedwith 1N NaOH, extracted with ethyl acetate, dried (MgSO₄), andconcentrated. Chromatography (silica, 1-5% methanol inmethylenechloride) gave 0.024 g (85%) of example 16A as a foam. MS: 535(M+H,100%); NMR (CDCl₃,300 MHz): δ 7.1-7.3 (m, 20H), 5.15 (d, 2H), 3.9(d, 2H), 3.5 (bs, 2H), 3.3-3.4 (m, 2H), 2.7-2.8 (m, 2H), 2.5-2.6 (m,2H), 2.0-2.1 (m, 6H).

Alternate Route to XXVIf:

Ester Hydrolysis: Synthesis of diacid LIVa

To a solution of 100.7 g (458.0 mmol) of(4R,5R)-(-)-dimethyl-2,3-O-isopropylidine-L-tartrate in 450 mL ofethanol was added 450 ml of 15% sodium hydroxide in water. Afterstirring 5 h the solvent was partially removed under reduced pressureand the residue was diluted with water and extracted with EtOAc. Theaqueous layer was then acidified with conc. HCl, saturated with NaCl,and extracted with EtOAc. The combined organic layers were washed withbrine and dried over MgSO4. The solvent was removed under reducedpressure and the solid residue was triturated with CH₂ Cl₂ and hexanesto give 72.2 g (83%) of the diacid LIVa as a white solid. mp 98°-100° C.¹ H NMR (300 MHz, CD₃ OD) δ 4.83 (s, 2H, CH), 1.54 (s, 6H, CH₃).

Preparation of Weinreb Amide: Synthesis of LIVb

To a solution of 30 g (157.8 mmol) of LIVa in 1 L of methylene chloridewas added 60 g (370.0 mmol) of 1,1'-carbonyldiimidazole. After stirring6 h, 34.0 g (350 mmol) of N,O-dimethylhydroxylamine hydrochloride wasadded and the resulting solution was stirred overnight. The solvent waspartially removed under reduced pressure and the residue was dilutedwith ethyl acetate, The solution was then acidified with 4N HCl,saturated with NaCl, and extracted with EtOAc. The combined organiclayers were washed with brine and dried over MgSO4. The solvent wasremoved under reduced pressure and the residue was triturated with ethylacetate and hexanes to give 35.6 g (82%) of the bis-Weinreb amide LIVbas a tan solid. mp. 78°-80° C. ¹ H NMR (300 MHz, CDCl₃) δ 5.16 (s, 2H,CH), 3.70 (s, 6H, OCH₃), 3.22 (s, 6H, CH₃), 1.52 (s, 6H, CH₃); MS(CI,NH₃) m/e 277 (M+1).

Addition of Grignard Reagent: Synthesis of diketone LIVc

To a solution of 4.0 g (14.5 mmol) of the LIVb in 100 mL of THF wasadded 20 mL (40 mmol) of 2M octylmagnesium bromide in THF dropwise.After stirring 3.5 h, the solution was quenched with saturated NH₄ Cl,acidified with 1N HCl, and was extracted with EtOAc. The combinedorganic layers were washed with brine and dried over MgSO4. The solventwas removed under reduced pressure and the residue was chromatographedon silica gel. Elution with 7.5% ethyl acetate in hexanes gave 4.86 g(88%) of the bis-octyl ketone LIVc as an oil. ¹ H NMR (300 MHz, CDCl₃) δ4.55 (s, 2H, CH), 2.64 (dt, 4H, CH₂), 1.62 (m, 4H, CH₂), 1.42 (s, 6H,CH₃), 1.27 (broad s, 20H, CH₂), 0.88 (t, 6H, CH₃); MS (CI,NH₃) m/e 383(M+1).

Oxime Formation: Synthesis of LIVd

To a solution of 4.65 g (12.2 mmol) of LIVc in 140 mL of ethanol and 35ml of water was added 2.22 g (32.2 mmol) of hydroxylamine hydrochloride.After stirring overnight the solvent was partially removed under reducedpressure and the residue was diluted with water and extracted withEtOAc. The combined organic layers were washed with brine and dried overMgSO4. The solvent was removed under reduced pressure and the residuewas chromatographed on silica gel. Elution with 15% ethyl acetate inhexanes gave 3.76 g (75%) of the bis-octyl oxime LIVd as a mix ofisomers. MS (CI,NH₃) m/e 413 (M+1).

Reduction of Oxime: Synthesis of diamine LIVe

To a solution of 3.68 g (8.9 mmol) of LIVd in 70 mL of toluene at 0° C.was added 53 mL (80 mmol) of 1.5M diisobutylaluminum hydride in tolueneover 15 min. and the solution was allowed to warm to room temperature.After stirring overnight the solution was quenched with saturatedRochelle's salt and gently stirred at room temperature. After stirringovernight the solution was extracted with EtOAc and dried over MgSO4.The solvent was removed under reduced pressure and the residue waschromatographed on silica gel. Elution with 10% methanol in methylenechloride gave 2.33 g (68%) of the diamine LIVe as an oil. ¹ H NMR (300MHz, CDCl₃) δ 3.80 (s, 2H, CH), 2.68 (m, 2H, CH), 1.43 (m, 4H, CH₂),1.41 (s, 6H, CH₃), 1.27 (broad s, 24H, CH₂), 0.88 (t, 6H, CH₃).

Cyclization of the Diamine: Formation of Cyclic Urea (XXVIf):

To a solution of 1.35 g (3.5 mmol) of LIVe in 50 mL of1,1,2,2-tetrachloroethane was added 620 mg (3.8 mmol) of1,1'-carbonyldiimidazole. After stirring 10 min the solution was addeddropwise over 30 min to 150 mL of refluxing 1,1,2,2-tetrachloroethane.The solution was cooled and was washed with dilute HCl, water, brine,and was dried over MgSO4 The solvent was removed under reduced pressureand the residue was chromatographed on silica gel. Elution with 33%ethyl acetate in hexanes increasing to 50% ethyl acetate in hexanes gave379 mg (27%) of the cyclic urea XXVIf. ¹ H NMR (300 MHz, CDCl₃) δ 5.24(d, 2H, NH), 4.07 (s, 2H, CH), 3.33 (m, 2H, CH), 1.60 (m, 4H, CH₂), 1.43(s, 6H, CH₃), 1.26 (broad s, 24H, CH₂), 0.88 (t, 6H, CH₃); MS (CI,NH₃)m/e 411 (M+1).

Example 15AJ

Alkylation of the cyclic urea XXVIf and removal of the acetonideprotecting group was carried out using the procedures described above togive compound 15AJ in a 68% yield. mp. 66°-70° C. ¹ H NMR (300 MHz,CDCl₃) δ 7.32 (m, 10H, aromatic),5.15 (d, 2H, CH₂), 3.87 (d, 2H, CH₂),3.46 (s, 2H, CH), 3.26 (br d, 2H, CH), 1.96 (s, 2H, OH), 1.60 (m, 4H,CH₂), 1.26 (m, 24H, CH₂), 0.89 (t, 6H, CH₃); MS (CI,NH₃) m/e 551 (M+1).

                                      TABLE 2e                                    __________________________________________________________________________     ##STR79##                                                                    Ex. Stereo                       K.sub.i                                      No. 2:3:4:5                                                                           R.sup.22  R.sup.23 R.sup.4 = R.sup.7                                                                   HPLC                                                                              Note                                     __________________________________________________________________________    16A RSSR                                                                              benzyl    benzyl   phenethyl                                                                           ++  1                                        16B RSSR                                                                              allyl     allyl    phenethyl                                                                           +   1                                        16C RSSR                                                                              allyl     allyl    isopropyl                                                                           ++  2                                        16D RSSR                                                                              cyclopropyl                                                                             cyclopropyl                                                                            isopropyl                                                                           ++  2                                                methyl    methyl                                                      16E RSSR                                                                              allyl     allyl    methyl                                                                              +   2                                        16F RSSR                                                                              allyl     n-butyl  methyl                                                                              +   2                                        16G RSSR                                                                              benzyl    benzyl   methyl                                                                              +   2                                        16H RSSR                                                                              2-naphthyl-                                                                             2-naphthyl-                                                                            methyl                                                                              +   2                                                methyl    methyl                                                      16I RSSR                                                                              allyl     allyl    isobutyl                                                                            +++ 2                                        16J RSSR                                                                              cyclopropyl                                                                             cyclopropyl                                                                            isobutyl                                                                            +++ 2                                                methyl    methyl                                                      16K RSSR                                                                              benzyl    benzyl   2-naphthyl                                                                          +++ 1                                                                   methyl                                             16L RSSR                                                                              cyclopropyl                                                                             cyclopropyl                                                                            2-naphthyl                                                                          +++ 1                                                methyl    methyl   methyl                                             16M RSSR                                                                              3-cyanobenzyl                                                                           3-cyanobenzyl                                                                          2-naphthyl                                                                              1                                                                   methyl                                             16N RSSR                                                                              3,4-dihydroxy                                                                           3,4-dihydroxy                                                                          2-naphthyl                                                                              1                                                benzyl    benzyl   methyl                                             16O RSSR                                                                              cyclopropyl                                                                             cyclopropyl                                                                            2-thienyl                                                                           +++ 2                                                methyl    methyl   methyl                                             16P RSSR                                                                              3-        3-       2-thienyl                                                                           +++ 2                                                (H.sub.2 NC(═NOH))-                                                                 (H.sub.2 NC(NOH))-                                                                     methyl                                                     benzyl    benzyl                                                      16Q RSSR                                                                              benzyl    benzyl   4-    +++ 1                                                                   methylthio                                                                    benzyl                                             16R RSSR                                                                              3-        3-       2-methoxy                                                                           ++  1                                                methoxybenzyl                                                                           methoxybenzyl                                                                          benzyl                                             165 RSSR                                                                              cyclopropyl                                                                             cyclopropyl                                                                            2-methoxy                                                                           ++  1                                                methyl    methyl   benzyl                                             16T RSSR                                                                              benzyl    benzyl   2-methoxy                                                                           ++  1                                                                   benzyl                                             16U RSSR                                                                              benzyl    benzyl   4-        1                                                                   methylsulfo                                                                   nylbenzyl                                          16V RSSR                                                                              benzyl    benzyl   3-        1                                                                   aminobenzyl                                        16W RSSR                                                                              benzyl    benzyl   4-        1                                                                   aminobenzyl                                        16X RSSR                                                                              n-hexyl   n-hexyl  isopropyl                                                                           +++ 2                                        16Y RSSR                                                                              benzyl    benzyl   3-    ++  2                                                                   indolylmeth                                                                   yl                                                 16Z RSSR                                                                              benzyl    benzyl   isobutyl                                                                            ++  2                                        16AA                                                                              RSSR                                                                              benzyl    benzyl   2-    +   2                                                                   methylthio                                                                    ethyl                                              16AB                                                                              RSSR                                                                              cyclopropyl                                                                             cyclopropyl                                                                            2-    +   2                                                methyl    methyl   methylthio                                                                    ethyl                                              16AC                                                                              RSSR                                                                              benzyl    benzyl   1-benzyl-3-                                                                         ++  2                                                                   indolyl                                            16AD                                                                              RSSR                                                                              benzyl    benzyl   isobutyl                                                                            +++ 2                                        16AE                                                                              RSSR                                                                              n-butyl   n-butyl  isobutyl                                                                            ++  2                                        16AF                                                                              RSSR                                                                              4-        4-       2-    +   2                                                hydroxymethyl                                                                           hydroxymethyl                                                                          methylthio                                                 benzyl    benzyl   ethyl                                              16AG                                                                              RSSR                                                                              benzyl    benzyl   n-butyl                                                                             +   3                                        16AH                                                                              RSSR                                                                              benzyl    benzyl   n-pentyl                                                                            ++  3                                        16AI                                                                              RSSR                                                                              benzyl    benzyl   n-hexyl                                                                             ++  3                                        16AJ                                                                              RSSR                                                                              benzyl    benzyl   n-octyl                                                                             +   3                                        16AK                                                                              RSSR                                                                              benzyl    benzyl   3-butenyl                                                                           +   3                                        16AL                                                                              RSSR                                                                              benzyl    benzyl   4-pentenyl                                                                          +   3                                        16AM                                                                              RSSR                                                                              benzyl    benzyl   2-    ++  3                                                                   ethylbutyl                                         16AN                                                                              RSSR                                                                              benzyl    benzyl   5-hydroxy                                                                           +   3, 4                                                                pentyl                                             16AO                                                                              RSSR                                                                              benzyl    benzyl   4-hydroxy                                                                           +   3, 4                                                                butyl                                              16AP                                                                              RSSR                                                                              allyl     allyl    n-octyl                                                                             ++  3                                        16AQ                                                                              RSSR                                                                              allyl     allyl    n-hexyl                                                                             +   3                                        16AR                                                                              RSSR                                                                              allyl     allyl    4-pentenyl                                                                          +   3                                        16AS                                                                              RSSR                                                                              allyl     allyl    3-butenyl                                                                           +   3                                        16AT                                                                              RSSR                                                                              4-        4-       n-butyl                                                                             ++  3                                                hydroxymethyl                                                                           hydroxymethyl                                                       benzyl    benzyl                                                      __________________________________________________________________________     Note 1: Prepared as in Scheme 4.                                              Note 2: Prepared as compounds in Table 1A.                                    Note 3: Prepared as in Scheme 28.                                             Note 4: Prepared by hydroboration of the corresponding alkene.           

Listed below are physical data for representative compounds of theinvention.

Example 16A: MS: 535 (M+1, 100%); NMR (CDCl₃,300 MHz): δ 7.1-7.3 (m,20H), 5.15 (d, 2H), 3.9 (d, 2H), 3.5 (bs, 2H), 3.3-3.4 (m, 2H), 2.7-2.8(m, 2H), 2.5-2.6 (m, 2H), 2.0-2.1 (m, 6H).

Example 16B: MS: 435 (M+1, 100%); NMR (CDCl₃,300 MHz): δ 7.1-7.3 (m,10H), 5.8 (m, 2H), 5.15 (s, 2H), 5.1 (d, 2H), 4.5-4.6 (m, 2H), 3.8 (s,2H), 3.3-3.5 (m, 4H), 2.5-2.9 (m, 4H), 2.2 (m, 2H), 2.0 (m, 4H).

Example 16C: MS: 312 (22, M+2), 311 (100, M+1), 267 (1). HRMS: Calc.311.2334. Found: 311.2330. NMR (CDCl₃): δ 5.81(m, 2H), 5.2(m, 4H),4.4(m, 2H), 4.0(br s, 2H), 3.4 (m, 2H), 3.1(br s, 2H), 3.0(m, 2H),2.4(m, 2H), 1.2(d, 6H), 0.9(d, 6H).

Example 16D: MS: 341(4), 340 (25), 339 (100, M+1), 321 (1), 295 (2), 256(2). HRMS: Calc. 339.2647. Found: 339.2652. NMR (CDCl₃): δ 4.2(brs, 2H),3.65(m, 2H), 3.20(m, 4H), 2.6(m, 4H), 1.2(d, 6H), 1.0(m, 2H), 0.9(d,6H), 0.5(m, 4H), 0.2(m, 4H).

Example 16E: MS: 256 (15, M+2), 255 (100, M+1). HRMS: Calc. 255.1706.Found: 255.1708. NMR (CDCl₃) δ 5.8(m, 2H), 5.2(m, 4H), 4.0(m, 2H),3.8(br s, 2H), 3.65(m, 2H), 3.4(m, 2H), 2.8(m, 2H), 1.2(d, 6H).

Example 16F: MS: 272 (16, M+2), 271 (100, M+1). HRMS: Calc. 271.2021.Found: 271.2036. NMR (CDCl₃): δ 5.8(m, 1H), 5.2(m, 2H), 4.0(m, 2H),3.8(br s, 2H), 3.6-3.3(3H), 3.0(m, 2H), 2.45(m, 2H), 1.35(m, 2H), 1.2(d,6H), 0.9(m, 4H).

Example 16G: MS: 356 (23, M+2), 355 (100, M+1). HRMS: Calc. 355.2021.Found: 355.2012. NMR (CDCl₃): δ 7.4-7.2(m, 10H), 4.9(d, 2H), 4.2(d, 2H),3.6(br s, 2H), 3.3(m, 2H), 2.2(m, 2H), 1.2(d, 6H).

Example 16H: mp 236°-238° C. MS: 456 (29, M+2), 455 (100, M+1), 315(10), 158 (5). HRMS: 455.2334. Found: 455.2333. NMR (CDCl₃): δ7.9-7.8(m, 8H), 7.6-7.45(m, 6H), 5.0(d, 2H), 4.4(m, 2H), 3.6(br s, 2H),3.4(m, 2H), 1.9(m, 2H), 1.2(m, 2H).

Example 16I: MS 339 (100, M+1), 311 (4). HRMS 339.265377 (calc.mass=339.264768). NMR (CDCl₃): δ 5.91-5.79 (m), 5.29-5.18 (m, 4H),4.53-4.46 (m, 2H), 3.76 (s, 2H), 3.41-3.33 (m, 4H), 2.13 (s, 2H),1.81-1.71 (m, 2H), 1.71-1.62 (m, 2H), 1.45-1.35 (m, 2H), 0.90 (t, 12H).

Example 16J: m.p. 137°-139° C. MS 367 (100, M+1). HRMS 367.295357 (calc.mass=367.296068). NMR (CDCl₃): δ 3.94 (s, 2H), 3.82 (d, 2H), 3.77 (d,2H), 3.48 (d, 2H), 2.91 (bs, 2H), 2.63 (d, 2H), 2.61 (d, 2H), 1.99 (m,2H), 1.70-1.61 (m, 2H), 1.43 (m, 2H), 1.26 (s, 2H), 1.07-0.98 (m, 2H),0.91 (t, 12H), 0.52 (m, 2H), 0.22 (m, 2H).

Example 16Q: mp 214° C.

Example 16R: mp 192°-193° C.

Example 16S: mp 155°-156° C.

Example 16T: mp 194°-195° C.

Example 16U: mp 244° C.

Example 16X: mp 112°-113° C. MS 427 (100, M+1)

Example 16Y: MS: 585.2 (100, M+H). NMR(CDCl₃) δ 8.02 (s, 2H), 7.55 (d,2H), 7.4 (d, 2H), 7.01 (m, 4H), 6.79 (s, 2H), 4.84 (d, 2H), 3.78 (s,4H), 3.2 (m, 6H)

Example 16Z: MS: 475.2 (100, M+H). NMR(CDCl₃) δ 7.48-7.22 (m, 10H),4.76-4.4 (dd, 4H), 3.8 (s, 2H), 3.62 (m, 2H), 2.23 (s, 2H), 1.73 (m,2H), 1.59 (m, 4H), 1.36 (m, 4H), 0.76 (d, 6H), 0.61 (d, 6H)

Example 16AA: MS: 475.0 (100, M+H). NMR(CDCl₃) δ 7.41-7.18 (m, 10H),5.01 (d, 2H), 4.01 (d, 2H), 3.65-3.41 (m, 5H), 3.01 (dd, 1H), 2.6-2.3(m, 6H), 2.0 (m, 6H), 1.25 (m, 2H)

Example 16AB: MS: 403.2 (100, M+H). NMR(CDCl₃) δ 3.97 (s, 2H), 3.8-3.6(m, 4H), 2.8-2.4 (m, 8H), 2.24 (m, 2H), 1.62 (s, 2H), 1.03 (m, 2H), 0.52(m, 4H), 0.32-0.14 (m, 4H)

Example 16AC: MS: 765.5 (59, M+H) 382.1 (100), 274 (97). NMR(CDCl₃) δ7.53 (d, 2H), 7.35-7.0 (m, 26H), 6.63 (s, 2H), 5.24 (s, 2H), 5.23 (s,2H), 4.82 (d, 2H), 3.8 (s, 4H), 3.3-3.08 (m, 6H), 2.37 (s, 2H)

Example 16AD: MS: 439.2 (M+H) NMR(CDCl₃) δ 7.39-7.28 (m,10H), 5.19 (d,4H), 3.85 (d, 4H), 3.50 (s, 2H), 3.38 (d, 2H), 1.95 (s, 2H), 1.75 (m,4H), 1.38 (m, 2H), 0.92 (d, 6H), 0.85 (d, 6H)

Example 16AD: MS: 439.2 (M+H). NMR(CDCl₃) δ 7.39-7.28 (m,10H), 5.19 (d,4H), 3.85 (d, 4H), 3.50 (s, 2H), 3.38 (d, 2H), 1.95 (s, 2H), 1.75 (m,4H), 1.38 (m, 2H), 0.92 (d, 6H), 0.85 (d, 6H) MS: (M+H)+=439.2

Example 16AE: MS: 371 (M+H). NMR(CDCl₃) δ 4.0 (m, 2H), 3.85 (s, 2H),3.35 (d, 2H), 2.65 (m, 2H), 2.35 (s, 2H), 1.82 (m, 2H), 1.75-1.24 (m,12H), 0.91 (m, 18H)

Example 16AF: MS: 552 (100, M+NH₄), 535 (61, M+H), 516 (81). NMR(CDCl₃)δ 7.38 (d, 8H), 5.05 (d, 2H), 4.68 (s, 4H), 3.98 (d, 2H), 3.65 (s, 2H),3.52 (m, 2H), 3.43 (s, 2H), 2.57 (m, 2H), 2.42 (m, 2H), 2.03 (s, 6H),1.97 (m, 4H), 0.84 (m, 4H)

Example 16AG: mp 109°-114° C. MS m/e 439 (M+H)

Example 16AH: mp 94°-97° C. MS m/e 467 (M+H)

Example 16AI: mp 79°-82° C. MS m/e 495 (M+H)

Example 16AJ: mp 66°-70° C. MS m/e 551 (M+H)

Example 16AK: mp 123°-126° C. MS m/e 435 (M+H)

Example 16AL: MS m/e 463 (M+H).

Example 16AM: mp 91°-94° C. MS m/e 495 (M+H)

Example 16AN: mp 111°-116° C. MS m/e 499 (M+H)

Example 16AO: MS m/e 483 (M+H)

Example 16AP: mp 73°-74° C. MS m/e 451 (M+H)

Example 16AQ: mp 73°-75° C. MS m/e 395 (M+H)

Example 16AR: mp 108°-111° C. MS m/e 363 (M+H)

Example 16AS: mp 110°-114° C. MS m/e 335 (M+H)

Example 16AT: mp 114°-116° C. MS m/e 499 (M+H)

The structures of the Examples below are shown in Table 2f-h.

Synthesis of Thiourea (XXVIIa):

Diaminodimem Compound (XXIc) (22.45 g, 47.1 mmol) was dissolved in 200mL of tetrahydrofuran and to this solution was added 9.23 g (51.8 mmol)of thiocarbonyl diimidazole. After stirring the mixture for 18 hours atroom temperature TLC (10:1:10 ethyl acetate:ethanol:hexane) indicatedcomplete reaction. The reaction mixture was taken to dryness and thesolid residue purified by flash chromatography (silica gel, 250 g, 1:1ethyl acetate:hexane) to provide solid which was triturated with hexaneto provide 17.8 g (73% yield) of XXVIIa as a white solid.

Synthesis of Compound (XXVIIb):

Compound (XXVIIa) (3.108 g, 6 mmol) was dissolved in 15 ml acetonitrileand to this solution was added methyl iodide 1.5 ml (24 mmol) viasyringe and stirred at room temperature for one hour. The contents werethen taken to dryness. The residue was dissolved in 30 mldimethylformamide and to this solution, cooled in a 0° C. ice bath, wasadded NaH (60% in oil) 720 mg (18 mmol) slowly (EVOLUTION|). Thecontents were stirred at room temperature for 30 minutes. The mixturewas cooled in a 0° C. ice bath and benzyl bromide (2.052 g, 12 mmol) wasadded via syringe and stirred at room temperature for 18 hours. TLC (2:3EtOAc:Hexane R_(f) =0.25) indicated a complete reaction. The reactionwas worked up by diluting with water (300 ml) and extracting withdiethyl ether (3×50 ml). The organic layer was dried over magnesiumsulfate and the filtrate taken to dryness. The residue was purified onSiO₂ gel (200 g; 2:3 EtOAc:Hexane) to provide 2.923 g (78.2% yield) ofXXVIIb as a colorless oil.

Synthesis of Compounds (XXVIIc) and (XXVIId):

Compound (XXVIIb) (2.900 g, 4.65 mmol) was dissolved in 25 ml pyridineand to this solution was added 742 mg (4.65 mmol) benzylhydroxylaminehydrochloride. The contents were refluxed in a 125° C. oil bath for 18hours. (Caution: Methyl mercaptan is a by-product and the reactionshould be vented to a Clorox scrubber). TLC indicated a completereaction. The reaction was diluted with 150 ml dichloromethane. Theorganic layer was washed with 1N HCl (2×300 ml) followed by sat. sodiumbicarbonate solution (100 ml). It was separated and dried over magnesiumsulfate and the filtrate taken to dryness. The residue was purified onSiO₂ gel(130 g; using 1:3 EtOAc:Hexane) to provide 584 mg (18.0% yield)of Compound (XXVIIc) as a colorless oil. 1:2 EtOAc:Hexane was used toprovide 2.113 g of a side product thiourea (XXVIId).

Synthesis of Oxime (XXVIIe):

Compound (XXVIIc) (584 mg, 0.84 mmmol) was dissolved in 5 mldimethylformamide and to this solution, cooled in a 0° C. ice bath, wasadded NaH(60% in oil) 80 mg (2 mmol) slowly (EVOLUTION|). The contentswere stirred at room temperature for 30 minutes. The mixture was cooledin a 0° C. ice bath and benzyl bromide (0.24 ml, 2 mmol) was added viasyringe and stirred at room temperature for 18 hours. TLC (1:3EtOAc:Hexane R_(f) =0.26) indicated a complete reaction. The reactionwas worked up by diluting with water (50 ml) and extracting with diethylether (2×25 ml). The organic layer was dried over magnesium sulfate andthe filtrate taken to dryness. The residue was purified on SiO₂ gel (33g; 1:3 EtOAc:Hexane) to provide 491 mg (74.2% yield) of a colorless oil.

Example 18A

Compound (XXVIId) (450 mg, 0.57 mmol) was placed in a 25 ml R.B. Flaskand cooled in a 0° C. ice bath. To this flask was added 4M HCl indioxane (5 ml, 20 mmol) and the mixture stirred at room temperature for18 hours. TLC (2:3 EtOAc:Hexane R_(f) =0.29) indicated a completereaction. The mixture was worked up by quenching in sat.sodiumbicarbonate solution (50 ml) and extracting with dichloromethane (2×50ml). The organic extracts were dried over magnesium sulfate and thefiltrate taken to dryness. The residue was purified on SiO₂ gel(33 g;2:3 EtOAc:Hexane) to provide 246 mg (70.5% yield) of Example 18A as awaxy solid.

Example 17A

Example 18A (160 mg, 0.26 mmol) was dissolved in 5 ml ethanol. To thismixture was added 50 mg of 10% palladium hydroxide on Carbon and thesuspension stirred for 18 hours under hydrogen(1 atm). TLC (10:1:10EtOAc:EtOH:Hexane R_(f) =0.3) indicated a complete reaction. Thesuspension was filtered through a celite pad and the filtrate taken todryness. The residue was purified on SiO₂ gel (33 g; 10:1:10EtOAc:EtOH:Hexane) to provide 97 mg of Example 17A (69.5% yield) as awhite solid.

Example 19A

Compound (XXVIId) (500 mg, 0.82 mmol) was placed in a 25 ml R.B. Flaskand cooled in a 0° C. ice bath. To this flask was added 4M HCl indioxane (7.5 ml, 30 mmol) and the mixture stirred at room temperaturefor 18 hours. TLC (1:2 EtOAc:Hexane R_(f) =0.29) indicated a completereaction. The mixture was worked up by quenching in sat.sodiumbicarbonate solution (50 ml) and extracting - th dichloromethane (2×50ml). The organic extracts were dried over magnesium sulfate and thefiltrate taken to dryness. The residue was purified on SiO₂ gel (33 g;1:2 EtOAc:Hexane) to provide 181 mg (51.1% yield) of Example 19A as awhite solid.

                  TABLE 2f                                                        ______________________________________                                         ##STR80##                                                                    Ex.              HPLC                   MS                                    No.    R         Ki       IC.sub.90                                                                           m.p. °C.                                                                       M + H                                 ______________________________________                                        17A    CH.sub.2 C.sub.6 H.sub.5                                                                ++           120.1   522.275                                 ______________________________________                                    

                  TABLE 2g                                                        ______________________________________                                         ##STR81##                                                                    Ex.              HPLC                   MS                                    No.    R         Ki       IC.sub.90                                                                           m.p. °C.                                                                       M + H                                 ______________________________________                                        18A    CH.sub.2 C.sub.6 H.sub.5                                                                +            59.5    612.322                                 ______________________________________                                    

                  TABLE 2h                                                        ______________________________________                                         ##STR82##                                                                    Ex.              HPLC                   MS                                    No.    R         Ki       IC.sub.90                                                                           m.p. °C.                                                                       M + H                                 ______________________________________                                        19A    CH.sub.2 Ph                                                                             +++      +++   74.0                                          ______________________________________                                    

The structures of the Examples below are shown in Table 2i.

Acetylation of Diol: Compound (XXVIIIa):

Example 1X (3.517 g, 7.58 mmol) was dissolved in 25 ml pyridine and tothis solution, cooled in a 0° C. ice bath, was added 350 mg4-Dimethylaminopyridine and 7.16 ml (75.85 mmol) acetic anhydride. Thecontents were stirred at room temperature for 18 hours. TLC (1:4EtOAc:Hexane R_(f) =0.3) indicated a complete reaction. The reaction wasdiluted with 250 ml dichloromethane. The organic layer was washed with1N HCl (2×300 ml) followed by sat. sodium bicarbonate solution (100 ml).It was separated and dried over magnesium sulfate and the filtrate takento dryness. The residue was purified on SiO₂ gel (200 g; 1:5EtOAc:Hexane) to provide 2.632 g (67.0%) of XXVIIIa as a white solid.

Nitration of Benzyl Group: Compound (XXVIIIb) and (XXVIIIc):

Compound (XXVIIIa) (518 mg, 1 mmol) was dissolved in 4 ml acetonitrileand to this solution, cooled in a -40° C. dry ice-acetone bath, wasadded 4.4 ml (2.2 mmol) 0.5M Nitronium tetrafluoroborate in sulfolane.The contents were stored in a -40° C. freezer for 18 hours. TLCindicated a complete reaction. The reaction was diluted with 100 mlether and washed with water (2×50 ml). The organic layer was dried overmagnesium sulfate and the filtrate taken to dryness. The residue waspurified on SiO₂ gel (75 g; 1:3 EtOAC:Hexane for XXVIIIb, 1:2EtOAc:Hexane for XXVIIIc) to provide 106 mg (17.4% yield) of XXVIIIb asa white solid and 159 mg(26.2% yield) of XXVIIIc as a white solid.

Example 20A

Compound (XXVIIIb) (106 mg, 0.174 mmol) was dissolved in 5 ml methanoland to this solution was added 0.5 ml 0.5M sodium methoxide in methanolvia syringe. The contents were stirred at room temperature for 30minutes. TLC indicated a complete reaction. The mixture was quenched byadding 500 mg of AG50W-X8 acid resin and stirring the suspension at roomtemperature for 5 minutes. The filtrate was taken to dryness and theresidue purified on SiO₂ gel (33 g; 1:2 EtOAc:Hexane) to provide 43 mg(47.1% yield) of Example 20A as a white solid.

Example 20B

Compound (XXVIIIc) (159 mg, 0.261 mmol) was dissolved in 5 ml methanoland to this solution was added 0.5 ml 0.5M sodium methoxide in methanolvia syringe. The contents were stirred at room temperature for 30minutes. A white precipitate started forming after 15 minutes. TLCindicated a complete reaction. The mixture was quenched by adding 500 mgof AG50W-X8 acid resin and stirring the suspension at room temperaturefor 5 minutes. 10 ml dichloromethane was then added to solubilize thesolid. The filtrate was taken to dryness and the residue provided lllmg(81.1% yield) of Example 20B as a white solid.

Example 20E

Example 20A (100 mg, 0.191 mmol) was dissolved in 5 ml ethanol. To thismixture was added 50 mg of 5% palladium on Carbon and the suspensionstirred for 18 hours under hydrogen(1 atm). TLC indicated a completereaction. The suspension was filtered through a celite pad and thefiltrate taken to dryness. The residue provided 47 mg (53.0% yield) ofExample 20E as a white solid.

Example 20F

Example 20B (100 mg, 0.191 mmol) was suspended in 5 ml ethanol. To thismixture was added 50 mg of 5% palladium on Carbon and the suspensionstirred for 18 hours under hydrogen(1 atm). The starting material wentinto solution as the reaction progressed. TLC indicated a completereaction. The suspension was filtered through a celite pad and thefiltrate taken to dryness. The residue provided 49 mg (55.2% yield) ofexample 20F as a white solid.

Example 20G

A. Synthesis of 4-Fluorobenzyl Cyclic Urea (XXXI): ##STR83##

The synthesis of 4-fluorobenzyl cyclic urea is outlined in Scheme 7.N-acetyl-D-4-fluorophenylalanine methyl ester (23.9 g, 0.1 mol),obtained using the procedure of M. J. Burk (J. Am. Chem. Soc. 1991, 113,8518), was dissolved in 40 mL of acetic acid and treated with 100 mL ofconcentrated HCl, 40 mL of water and heated to reflux for 5 hrs. Thesolution was cooled to room temperature and then made basic (pH=10) with50% NaOH while cooling in an ice bath. Benzyl chloroformate (25 mL, 29g, 0.17 mol) and NaOH are added in four portions and the solution ismaintained alkaline by the addition of NaOH. The mixture is then stirredat rt for 30 min. The alkaline solution is extracted with ether (2×500mL) and the solution acidified with conc HCl to pH 1. The precipitate isextracted into methylene chloride and dried over MgSO₄. The solution isfiltered and concentrated to give 20 g of theN--Cbz--D-4-fluorophenylalanine as a white solid that is used withoutfurther purification.

A solution of N,O-dimethylhydroxylamine hydrochloride (8.0 g, 0.082 mol)in DMF is prepared by gentle warming. The solution is allowed to coolslightly and treated with N-methylmorpholine (8.2 g, 0.082 mol) anddiluted with THF to facilitate transfering of the resulting thicksuspension.

A solution of N--Cbz--D-4-fluorophenylalanine (20 g, 0.063 mol) in THFis treated with N-methylmorpholine (9.0 g 0.09 mol) and cooled to 0° C.in an ice bath. To the stirred cold solution is added isobutylchloroformate (8.6 g, 0.063 mol) in small portions over a period of 10mins. Then the solution of N,O-dimethylhydroxylamine in DMF preparedabove is added and the reaction mixture is stirred for 20 mins. Most ofthe solvent is removed on a rotorary evaporator and the residue ispartitioned between water and methylene chloride. The organic layer iswashed successively with 1N HCl, 1N NaOH, water, brine and then driedover MgSO₄. The solution is then filtered and concentrated and theresidue chromatographed on silica gel (50% EtOAc/Hex) to give 16 g ofthe amide.

Using the procedure of by J-A. Fehrentz and B. Castro (Synthesis, 1983,676) 11 g (0.031 mol) of N--Cbz--D-4-fluorophenyl-alanineN,O-dimethylhydroxylamide was converted to 9.0 g ofN--Cbz--D-4-fluorophenylalaninal obtained as a thick oil that was usedwithout further purification.

N--Cbz--D-4-fluorophenylalaninal (9.0 g , 0.031 mol) was converted,using procedure 1, to(2R,3S,4S,5R)-2.5-bis(N--Cbz-amino)-3,4-dihydroxy-1,6-di(4-fluorophenyl)hexane(4 g) obtained as a white solid. MS: (CI, NH₃) (M+H)⁺ =605.

The(2R,3S,4S,5R)-2,5-bis(N--Cbz-amino)-3,4-dihydroxy-1,6-di(4-fluorophenyl)hexane(4.0 g, 0.0066 mol) was converted, as described in procedure 4, to 1.3 gof the 4-fluorobenzyl cyclic urea (XXXI) obtained as a white solid. MS:(CI, NH₃) (M+H)⁺ =539.3

B. The 4-fluorobenzyl cyclic urea (XXXI) (270 mg, 0.5 mmol) wasalkylated with 3-benzoxybenzyl chloride (350 mg, 1.5 mmol) according togeneral procedure 5. The resulting intermediate was dissolved in THF andhydrogenated for 12 hours (200 mg 10% Pd/C, 55 psi) to remove the benzylprotecting groups. The MEM group was then removed, according to generalprocedure 5, to give, after chromatography on HPLC (silica gel, 10%MeOH/CHCl₃), 140 mg of Example 20G as a white foam. MS: (CI, NH₃) (M+H)⁺=575.2 (100%).

Example 20W

By variation of the above-described methods, the title compound wasprepared. NMR (CDCl₃): δ 7.12-7.32 (m, 12H) 6.61-6.83 (m, 6H) 4.91 (d,2H) 3.80 (s, 6H) 3.64 (m,2H) 3.55 (m, 2H) 3.10 (d, 2H) 3.00 (m, 4H) 2.11(s, 2H).

                                      TABLE 2i                                    __________________________________________________________________________     ##STR84##                                                                                                     Mass                                                                          Spec                                         Ex.                    HPLC   m.p.                                                                             M + H                                        No. R.sup.22, R.sup.23                                                                     R.sup.4                                                                            R.sup.7                                                                            Ki  IC.sub.90                                                                        °C.                                                                       (M + NH.sub.4)                               __________________________________________________________________________    20A cyclopropyl-                                                                           4-nitro-                                                                           2-nitro-                                                                           +++ +++                                                                              209.8                                                                            525.234                                          methyl   benzyl                                                                             benzyl                                                      20B cyclopropyl-                                                                           4-nitro-                                                                           4-nitro-                                                                           +++ +++                                                                              227.5                                                                            525.234                                          methyl   benzyl                                                                             benzyl                                                      20C n-butyl  4-nitro-                                                                           2-nitro-                                                                           +++ +++                                                                              165.0                                                                            529.266                                                   benzyl                                                                             benzyl                                                      20D n-butyl  4-nitro-                                                                           4-nitro-    245.0                                                                            529.266                                                   benzyl                                                                             benzyl      (dec)                                           20E cyclopropyl-                                                                           4-amino-                                                                           2-amino-                                                                           +++ +++   465.286                                          methyl   benzyl                                                                             benzyl                                                      20F cyclopropyl-                                                                           4-amino-                                                                           4-amino-                                                                           ++  +++   465.286                                          methyl   benzyl                                                                             benzyl                                                      20G 3-hydroxy                                                                              4-fluoro                                                                           4-fluoro                                                                           +++       575.2                                            benzyl   benzyl                                                                             benzyl                                                      20H cyclopropyl-                                                                           4-fluoro                                                                           4-fluoro                                                                           +++       471.2                                            methyl   benzyl                                                                             benzyl                                                      20I 4-hydroxy                                                                              4-fluoro                                                                           4-fluoro                                                                           +++       603.2                                            methylbenzyl                                                                           benzyl                                                                             benzyl                                                      20J 4-acetyl benzyl                                                                             benzyl                                                                             ++        (608)                                            benzyl                                                                    20K 4-fluoro benzyl                                                                             benzyl                                                                             +++ +++   571                                              methylbenzyl                                                              20L 3-(H.sub.2 NC(O))-                                                                     4-fluoro                                                                           4-fluoro                                                                           +++ +++   (646.4)                                          benzyl   benzyl                                                                             benzyl                                                      20M 4-(CH.sub.3 CH(OH))-                                                                   benzyl                                                                             benzyl                                                                             +++ +++   595.2                                            benzyl                                                                    20N 3-(CH.sub.3 C(O))-                                                                     4-fluoro                                                                           4-fluoro                                                                           +++ +++   (644.4)                                          benzyl   benzyl                                                                             benzyl                                                      20O 3-cyano-benzyl                                                                         4-fluoro                                                                           4-fluoro                                                                           ++  +++   (610.2)                                                   benzyl                                                                             benzyl                                                      20P 3-(CH.sub.3 CH.sub.2 CH.sub.2                                                          4-fluoro                                                                           4-fluoro                                                                           +++ +++   (700.5)                                          C(O))-benzyl                                                                           benzyl                                                                             benzyl                                                      20Q                                                                                ##STR85##                                                                             benzyl                                                                             benzyl                                                                             +++ +++   671.4                                        20R                                                                                ##STR86##                                                                             benzyl                                                                             benzyl                                                                             ++  +++                                                                              779.4                                           20S                                                                                ##STR87##                                                                             4-fluoro benzyl                                                                    4-fluoro benzyl                                                                    ++  ++    815.5                                        20T 3-(HOCH.sub.2)-                                                                        4-fluoro                                                                           4-fluoro                                                                           +++ +++   603.3                                            benzyl   benzyl                                                                             benzyl                                                      20U 3-(CH.sub.3 C(NOH))-                                                                   4-fluoro                                                                           4-fluoro                                                                           +++ +++   657.5                                            benzyl   benzyl                                                                             benzyl                                                      20V 3-(H.sub.2 NC(NOH))-                                                                   benzyl                                                                             benzyl                                                                             +++ +++   623.3                                            benzyl                                                                    20W benzyl   3-   3-   +++ +++                                                             methoxy-                                                                           methoxy-                                                                 benzyl                                                                             benzyl                                                      20X 3-(H.sub.2 NC(NOH))-                                                                   4-fluoro                                                                           4-fluoro                                                                           +++ +++   659.3                                            benzyl   benzyl                                                                             benzyl                                                      20Y 3-       3,4- 3,4- +++ +++   695.4                                            carbomethoxyben                                                                        difluoro                                                                           difluoro                                                        zyl      benzyl                                                                             benzyl                                                      20Z 4-       3,4- 3,4- ++  +++   (712.4                                           carbomethoxyben                                                                        difluoro                                                                           difluoro       )                                                zyl      benzyl                                                                             benzyl                                                      20AA                                                                              3-hydroxymethyl                                                                        3,4- 3,4- +++ +++   639.4                                            benzyl   difluoro                                                                           difluoro                                                                 benzyl                                                                             benzyl                                                      20AB                                                                              4-hydroxymethyl                                                                        3,4- 3,4- +++ +++   639.4                                            benzyl   difluoro                                                                           difluoro                                                                 benzyl                                                                             benzyl                                                      20AC                                                                              3-(H.sub.2 NC(O))-                                                                     3,4- 3,4- +++ +++   665.2                                            benzyl   difluoro                                                                           difluoro                                                                 benzyl                                                                             benzyl                                                      20AD                                                                              3-(H.sub.2 NC(NOH))-                                                                   3,4- 3,4- +++ +++   695.                                             benzyl   difluoro                                                                           difluoro                                                                 benzyl                                                                             benzyl                                                      20AE                                                                              R.sup.22 =                                                                             4-fluoro                                                                           4-fluoro                                                                           +++ +++                                                                              123-                                                                             573.2                                            cyclopropyl                                                                            benzyl                                                                             benzyl      126                                                 methy                                                                         R.sup.23 =                                                                    3-(3-pyrazolyl                                                                benzyl                                                                    20AF                                                                              cyclopropyl                                                                            4-methoxy                                                                          4-methoxy                                                                          +++    145-                                                                             495                                              methyl   benzyl                                                                             benzyl      147                                             20AG                                                                              benzyl   4-methoxy                                                                          4-methoxy                                                                          +++       567                                                       benzyl                                                                             benzyl                                                      20AH                                                                              2-naphthyl                                                                             4-methoxy                                                                          4-methoxy                                                                          +++       667                                              methyl   benzyl                                                                             benzyl                                                      20AI                                                                              4-carbomethoxy                                                                         4-methoxy                                                                          4-methoxy                                                                          +         700                                              benzyl   benzyl                                                                             benzyl                                                      20AJ                                                                              4-hydroxymethyl                                                                        4-methoxy                                                                          4-methoxy                                                                          +++       644                                              benzyl   benzyl                                                                             benzyl                                                      20AK                                                                              benzyl   4-hydroxy                                                                          4-hydroxy                                                                          +++    179-                                                                             539                                                       benzyl                                                                             benzyl      180                                             20AL                                                                              allyl    4-methoxy                                                                          4-methoxy                                                                          +++       467                                                       benzyl                                                                             benzyl                                                      20AM                                                                              benzyl   4-(2-                                                                              4-(2-                                                                              +++    129-                                                                             627                                                       hydroxy                                                                            hydroxy     131                                                                              (644)                                                     ethoxy)                                                                            ethoxy)                                                                  benzyl                                                                             benzyl                                                      20AN                                                                              benzyl   4-(2-                                                                              4-(2-                                                                              +++    101-                                                                             765                                                       morpholin                                                                          hydroxy     103                                                          ylethoxy)                                                                          ethoxy)                                                                  benzyl                                                                             benzyl                                                      20AO                                                                              H        3-methoxy                                                                          3-methoxy                                                                          ++  ++ 205.4                                                                            387                                                       benzyl                                                                             benzyl                                                      20AP                                                                              n-butyl  3-hydroxy                                                                          3-hydroxy                                                                          ++  +  182.1                                                                            541                                                       benzyl                                                                             benzyl                                                      20AQ                                                                              3-hydroxy                                                                              3-hydroxy                                                                          3-hydroxy                                                                          +++ +++                                                                              181.2                                                                            571                                              benzyl   benzyl                                                                             benzyl                                                      20AR                                                                              n-butyl  3-   3-   +++    101.3                                                                            581                                                       (H.sub.2 NC(O)                                                                     (H.sub.2 NC(O)                                                           CH.sub.2 O)                                                                        CH.sub.2 O)                                                              benzyl                                                                             benzyl                                                      20AS                                                                              cyclopropyl                                                                            3-methoxy                                                                          3-methoxy                                                                          +++ +++   495                                              methyl   benzyl                                                                             benzyl                                                      20AT                                                                              4-hydroxy                                                                              3-methoxy                                                                          3-methoxy                                                                          +++ +++   627                                              methylbenzyl                                                                           benzyl                                                                             benzyl                                                      20AU                                                                              3-methoxy                                                                              3-methoxy                                                                          3-methoxy                                                                          +++ +++   627                                              benzyl   benzyl                                                                             benzyl                                                      20AV                                                                              cyclopropyl                                                                            3-   3-   ++        639                                              methyl   (EtOC(O)                                                                           (EtOC(O)                                                                 CH.sub.2 O)                                                                        CH.sub.2 O)                                                              benzyl                                                                             benzyl                                                      __________________________________________________________________________

The structures of the Examples below are shown in Table 2j.

Example 21A

A. Synthesis of Aziridine Urea (XXXIIa):

A solution of Example 1A (5.3 g, 0.016 mol) in pyridine was treated withacetic anhydride (3.3 g, 0.033 mol) and strirred at room temperature for3 hrs. 10 mL of MeOH was added and the mixture was evaporated todryness. The residue was extracted into methylene chloride and washedsequentially with water, 1N HCl, brine, and dried over MgSO₄. Thesolution was filtered, concentrated and the residue chromatographed onsilica gel (5% MeOH/CHCl₃) to give 2.0 g of the correspondingmonoacetate product as a white solid. The solid obtained was dissolvedin methylene chloride and cooled in an ice bath under nitrogen. To thiswas added DAST (0.875 g, 0.005 mol) via syringe and the solution stirredfor 10 mins. The mixture was quenched with sat'd NaHCO₃ and the organiclayer washed with water and brine. The solution is dried over MgSO₄ thenfiltered and concentrated to give 1.9 g of the acetate aziridine(XXXIIa) which is used without further purification.

B. The acetate aziridine (XXXIIa) (100 mg. 0.29 mmol) is dissolved inMeOH (2 mL) and treated with 1N NaOH (0.5 ml) and stirred at rt for 30min. The mixture is diluted with water (20 mL) and extracted into CH₂Cl₂. The extract is washed with water and brine, dried over MgSO₄ thenfiltered and concentrated to give 30 mg of Example 21A as a white solid.MS: (CI, NH₃) (M+H)⁺ =309.0

Example 21B and 21C

The acetate aziridine (XXXIIa) (200 mg, 0.57 mmol) is alkylated withbenzyl bromide (120 mg, 0.69 mmol) according to Procedure 5 to give amixture of products. This was HPLC chromatographed on silica gel (50%EtOAc/Hex) to give first 50 mg of Example 21B as a white solid. MS: (CI,NH₃) (M+H)⁺ =309.0. This was followed by 30 mg of Example 21C, obtainedas a colorless oil. MS: (CI, NH₃) (M+H)⁺ =489.2.

                  TABLE 2j                                                        ______________________________________                                         ##STR88##                                                                                                          MS                                                                            M + H                                   Ex No. R.sup.22    R        K.sub.i                                                                            IC.sub.90                                                                          (M + NH.sub.4)                          ______________________________________                                        21A    H           H        +    ++/+ 309.0                                   21B    benzyl      Ac       +    ++/+ 441.0                                   21C    benzyl      benzyl   ++        489.2                                   21D    benzyl      H        +    ++/+ 399.1                                   21E    3-benzyloxy H        +    ++/+ 505.2                                          benzyl                                                                 21F    3-          H        +    +    424.2                                          cyanobenzyl                                                            21G    3-(H.sub.2 NC(O))                                                                         H        ++   ++   442.0                                          benzyl                                                                 21H    3-          H        ++   +++  (474)                                          H.sub.2 NC(NOH)b                                                              enzyl                                                                  ______________________________________                                    

The structures of the Examples below are shown in Table 2k.

Preparation of the Cyclic Urea (XXXIIIa): ##STR89##

A. Preparation of4-Amino-2-(t-butoxycarbonylamino)-1,5-diphenyl-3-(2-methoxyethoxymethyl)pentane.

A mixture of 595 mg (1.50 mmole) of4-azido-2-(t-butoxycarbonylamino-1,5-diphenyl-3-hydroxypentane (EP 0 402646 A1), 10 ml of dioxane, 0.2 ml (1.75 mmole) of MEM chloride, and 0.32ml (1.83 mmole) of diisopropylethylamine was heated at 80° C. for 16hrs. Evaporated the solvent and purified the residue by flashchromatography on silica gel with 85:15 hexane-ethyl acetate to give0.64 g (88%) of an oil. Mass spec (M+H)⁺ =485.2. This was reduced to thetitle compound with hydrogen using 100 mg of 10% Pd on carbon in 60 mlof ethyl acetate and 0.6 ml of acetic acid in 49% yield.

B. Preparation of 2,4-diamino-1,5-diphenyl-3-hydroxypentane.

The product from Part A (218 mg) was dissolved in 2 ml of ice cold 1:1trifluoroacetic acid-dichloromethane. After 1 hr the solution was pouredinto a mixture of sodium bicarbonate solution and ethyl acetate. Theethyl acetate extract yielded 163 mg of the desired diamino compound.

C. Cyclization of the Diamine

The product from Part B (146 mg), 75 mg of carbonyl diimidazole, and0.15 ml of diisopropylethylamine were dissolved in 2.5 ml of anydrousTHF and stirred at room temperature for 16 hrs. The solvent wasevaporated. The residue was purified by preparative TLC on silica gelwith 90:10 dichloromethane-methanol to give 108 mg (69%) of the cyclicurea. Mass spec (M+H)⁺ =385.1.

N-Alkylation of the Cyclic Urea (XXXIIIa):

D. The product from Part C (93 mg) was dissolved in 2.5 ml of anhydrousDMF, and 100 mg of 60% NaH in mineral oil was added. The mixture wasstirred for one hr. m-Benzyloxbenzyl chloride (350 mg) was added, andthe mixture was stirred for 16 hrs at room temperature. Water and ethylacetate were added. The ethyl acetate extract was washed with water,dried and evaporated The residue was purified by prep TLC on silica gelwith 60:40 hexane-ethyl acetate to give 105 mg (54%) of the desiredbis-alkylated product. Mass spec (M+H)⁺ =777.5

Deprotection of Protecting Groups (Example 22A):

The product from part δ (103 mg) was dissolved in 4N HCl/dioxane for 16hrs. The solution was evaporated and purified by prep TLC on silica gelwith 60:40 hexane-ethyl acetate. Mass spec (M+H)⁺ =689.4. The purifiedmaterial was hydrogenated for 16 hrs in the presence of 3 ml ethanol.0.2 ml of acetic acid, and 35 mg of 10% Pd on carbon to give Example22A. Mass spec (M+H)⁺ =509.25; calculated, 509.24.

    ______________________________________                                         ##STR90##                                                                                                            MS                                    Ex No. R.sup.22   R.sup.23   K.sub.i                                                                            IC.sub.90                                                                           M + H                                 ______________________________________                                        22A    m-(HO)     m-(HO)     ++       509.25                                         C.sub.6 H.sub.4 CH.sub.2                                                                 C.sub.6 H.sub.4 CH.sub.2                                    ______________________________________                                    

The structures of the Examples below are shown in Table 2m.

Example 23F

Synthesis of Intermediate (XXXIVa): Compound XXIC (2.846 g, 5.95 mmol)was dissolved in pyridine (37.5 mL) and to this solution was addedsulfamide (572 mg, 5.95 mmol). The contents were refluxed in a 125° C.oil bath for 18 hours. (Caution: Ammonia is a by-product and thereaction should be well vented). TLC(1:1 EtOAc:Hexane Rf=0.2) indicateda complete reaction. The reaction was diluted with 200 ml diethyl etherand the organic layer was washed with water(300 ml), followed by 1NHCL(2×100 ml) and sat. sodium bicarbonate solution (25 ml). The organiclayer was dried over magnesium sulfate and the filtrate taken todryness. The residue was purified on Silica gel (130 g; using 1:1EtOAc:Hexane followed by 20:1:20 EtOAc:EtOH:Hexane) to provide 2.412 g(75.3% yield) of the desired intermediate (XXXIVa) as a white solid.

Intermediate (XXXIVa) (269 mg, 0.5 mmol) was dissolved indimethylformamide (3 mL) and to this solution, cooled in a 0° C. icebath, was slowly added sodium hydride (60% in oil, 80 mg, 2 mmol)(EVOLUTION|). The contents were stirred at room temperature for 30minutes. The mixture was cooled in a 0° C. ice bath and(bromomethyl)cyclopropane (0.19 mL, 2 mmol) was added via syringe andstirred at room temperature for 18 hours. TLC(1:1 EtOAc:Hexane Rf=0.3)indicated a complete reaction. The reaction was worked up by dilutingwith water(50 mL) and extracting with diethyl ether (2×25 mL). Theorganic layer was dried over magnesium sulfate and the filtrate taken todryness. The residue was placed in a 50 ml R.B. flask and dissolved inmethanol (3 mL) and to the flask was added 4M HCl in dioxane (3 mL, 12mmol) and the mixture stirred at room temperature for 18 hours. TLC (2:3EtOAc:Hexane Rf=0.3) indicated a complete reaction. The mixture wasworked up by quenching in sat. sodium bicarbonate (25 ml) and extractingwith dichloromethane (2×25 mL). The organic extracts were dried overmagnesium sulfate and the filtrate taken to dryness. The residue waspurified on silica gel (55 g; 1:2 EtOAc:Hexane followed by 1:1) toprovide 129 mg (54.8% yield) of the title compound as a white solid.m.p.71°-72° C.

Example 23C

Intermediate (XXXIVa) from Example 23F (538 mg, 1.0 mmol) was dissolvedin N,N-dimethylformamide (5 mL) and to this solution, cooled in a 0° C.ice bath, was slowly added sodium hydride (60% in oil, 160 mg, 4 mmol)(EVOLUTION|). The contents were stirred at room temperature for 30minutes. The mixture was cooled in a 0° C. ice bath andm-benzyloxybenzyl chloride (931 mg, 4 mmol) was added as a solid and themixture stirred at room temperature for 18 hours. TLC (1:2 EtOAc:HexaneRf=0.25) indicated a complete reaction. The reaction was worked up bydiluting with water(100 mL) and extracting with diethyl ether (2×50 mL).The organic layer was dried over magnesium sulfate and the filtratetaken to dryness. The residue was purified on silica gel (75 g; 1:2followed by 1:1 EtOAc:Hexane) to provide 785 mg (84.3% yield) of theintermediate (XXXIVb) (where R²² =R²³ =m-benzyloxybenzyl) as a colorlessfoam.

Intermediate (XXXIVb) (700 mg, 0.75 mmol) was dissolved in methanol (3.5mL) and to this solution cooled in a 0° C. ice bath, was added 4M HCl indioxane (3.5 mL, 14 mmol) and the mixture stirred at room temperaturefor 18 hours. TLC (1:2 EtOAc:Hexane Rf=0.26) indicated a completereaction. The mixture was worked up by quenching in sat.sodiumbicarbonate (50 mL) and extracting with dichloromethane (2×50 mL). Theorganic extracts were dried over magnesium sulfate and the filtratetaken to dryness. The residue was purified on silica gel (75 g; 1:2followed by 2:3 EtOAc:Hexane) to provide 357 mg (63.1% yield) of thetitle compound as a white solid. m.p.194°-195° C.

Example 23D

Example 23C (257 mg, 0.34 mmol) was dissolved in a mixture of ethanol (5mL) and dioxane (5 mL). To the mixture was added palladium hydroxide onCarbon (20%, 100 mg) and the suspension stirred for 18 hours underhydrogen (1 atm). TLC(10:1:10 EtOAc:EtOH:Hexane Rf=0.3) indicated acomplete reaction. The suspension was filtered through a celite pad andthe filtrate taken to dryness. The residue was purified on silica gel(33 g; 1:1 EtOAc:Hexane followed by 20:1:20 EtOAc:EtOH:Hexane) toprovide 162 mg (82.9% yield) of the desired compound as a white solid.m.p.123°-124° C.

                                      TABLE 2m                                    __________________________________________________________________________     ##STR91##                                                                                                                         MassSpec                 Ex. Stereo                                           M + H                    No. 2.3.4.5                                                                           R.sup.22        R.sup.23        HPLC K.sub.i                                                                       IC.sub.90                                                                        mp, °C.                                                                     (M                       __________________________________________________________________________                                                         + NH.sub.4)              23A RSSR                                                                              H               H               +    ++ 253-255                                                                            363.1387                 23B RSSR                                                                              p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        +++  +++                                                                              189-190                                                                            603.2528                 23C RSSR                                                                              m-(C.sub.6 H.sub.5 CH.sub.2 O)C.sub.6 H.sub.4 CH.sub.2                                        m-(C.sub.6 H.sub.5 CH.sub.2 O)C.sub.6 H.sub.4                                 CH.sub.2        ++   ++ 194-195                                                                            755.3155                 23D RSSR                                                                              m-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                m-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                +++  +++                                                                              123-124                                                                            575.2216                 23E RSSR                                                                              allyl           allyl           ++   +++                                                                              112-113                                                                            443.2005                 23F RSSR                                                                              cyclopropylmethyl                                                                             cyclopropylmethyl                                                                             +++  +++                                                                              71-72                                                                              471.2318                 23G RSSR                                                                              n-butyl         n-butyl         +++  +++                                                                              oil  475.2631                 23H RSSR                                                                              2-naphthylmethyl                                                                              2-naphthylmethyl                                                                              +++  +++                                                                              211-212                                                                            643.2631                 23I RSSR                                                                              benzyl          benzyl          ++   +++                                                                              159-161                                                                            543.2306                 23J RSSR                                                                              p-(C.sub.6 H.sub.5 CH.sub.2 O)C.sub.6 H.sub.4 CH.sub.2                                        p-(C.sub.6 H.sub.5 CH.sub.2 O)C.sub.6 H.sub.4                                 CH.sub.2        +    ++      755.3147                 23K RSSR                                                                              p-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                p-(HO)C.sub.6 H.sub.4 CH.sub.2                                                                +++  +++                                                                              223-225                                                                            (592.2486)               23L RSSR                                                                              m-nitrobenzyl   m-nitrobenzyl   ++   +++                                                                              196-198                                                                            633.2014                 23M RSSR                                                                              m-aminobenzyl   m-aminobenzyl   +++  +++                                                                              212-214                                                                            573.2535                 23N RSSR                                                                              m-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        m-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        +++  +++     603.2540                 23Q RSSR                                                                              m-((CH.sub.3).sub.2 NCH.sub.2 CO)C.sub.6 H.sub.4 CH.sub.2                                     m-((CH.sub.3).sub.2 NCH.sub.2 CO)C.sub.6 H.sub.4                              CH.sub.2        +++  +++                                                                              137-139                                                                            743.3596                 23P RSSR                                                                              m-(CH.sub.3 OCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                m-(CH.sub.3 OCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                ++   ++ 152-154                                                                            631.2832                 23Q RSSR                                                                              m-(CHO)C.sub.6 H.sub.4 CH.sub.2                                                               m-(CHO)C.sub.6 H.sub.4 CH.sub.2                                                               +++  +++                                                                              91-93                                                                              599.2211                 23R RSSR                                                                              CH.sub.2 -tetrahydrofuran-3-yl                                                                CH.sub.2 -tetrahydrofuran-3-yl                                                                ++   +++                                                                              97-99                                                                              531.2533                 23S RSSR                                                                              m-(HONCH)C.sub.6 H.sub.4 CH.sub.2                                                             m-(HONCH)C.sub.6 H.sub.4 CH.sub.2                                                             +++  +++                                                                              105-107                                                                            (646.2708)               23T RSSR                                                                              m-(CH.sub.3 CO)C.sub.6 H.sub.4 CH.sub.2                                                       m-(CH.sub.3 CO)C.sub.6 H.sub.4 CH.sub.2                                                       +++  +++                                                                              96-99                                                                              627.2523                 23U RSSR                                                                              m-(HONC(CH.sub.3))C.sub.6 H.sub.4 CH.sub.2                                                    m-(HONC(CH.sub.3))C.sub.6 H.sub.4 CH.sub.2                                                    +++  +++                                                                              110-113                                                                            657.2739                 23V RSSR                                                                              CH.sub.3        CH.sub.3        +    ++/+                                                                             200-203                                                                            391.1696                 23W RSSR                                                                              CH.sub.2 CH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                             ++   ++ 182-185                                                                            419.2007                 23X RSSR                                                                              CH.sub.2 CH.sub.2 CH.sub.3                                                                    CH.sub.2 CH.sub.2 CH.sub.3                                                                    +++  +++                                                                              145-148                                                                            447.2316                 23Y RSSR                                                                              m-(CN)C.sub.6 H.sub.4 CH.sub.2                                                                m-(CN)C.sub.6 H.sub.4 CH.sub.2                                                                ++   +++                                                                              146-149                                                                            593.2227                 23Z RSSR                                                                              m-(2-(4-morpholino)-                                                                          m-(2-(4-morpholino)-                                                                          ++   +/++                                                                             119-122                                                                            855.4111                         ethylNHC(O))C.sub.6 H.sub.4 CH.sub.2                                                          ethylNHC(O))C.sub.6 H.sub.4 CH.sub.2                  23AA                                                                              RSSR                                                                              m-(2-(N,N-dimethylamino)-                                                                     m-(2-(N,N-dimethylamino)-                                                                     ++   ++ 127-130                                                                            771.3903                         ethylNHC(O))C.sub.6 H.sub.4 CH.sub.2                                                          ethylNHYC(O))C.sub.6 H.sub.4 CH.sub.2                 23AB                                                                              RSSR                                                                              m-(2-amino-4-thienyl)-C.sub.6 H.sub.4 CH.sub.2                                                m-(2-amino-4-thienyl)-C.sub.6 H.sub.4 CH.sub.2                                                +++  +++                                                                              185-190                                                                            739                      23AC                                                                              RSSR                                                                              5-hydroxypentyl 5-hydroxypentyl +++  +++     (552)                    23AD                                                                              RSSR                                                                              6-hydroxypentyl 6-hydroxypentyl +++  +++     (580)                    23AE                                                                              RSSR                                                                              5-hydroxypentyl H               ++   ++/+    (466)                    23AF                                                                              RSSR                                                                              5-hydroxypentyl 2-naphthylmethyl                                                                              +++  +++     (606)                    23AG                                                                              RSSR                                                                              5-hydroxypentyl p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        +++  +++     (586)                    23AH                                                                              RSSR                                                                              5-hydroxypentyl p-(HOCH.sub.2)C.sub.6 H.sub.4 CH.sub.2                                                        +++  +++     (586)                    __________________________________________________________________________

The structures of the Examples below are shown in Table 2n.

Intermediate (XXXIVb): To a solution of diamine (XXIC) (100 mg, 0.21mmol.) in ethanol (3 mL), was added p-toluenesulfonic acid monohydrate(39 mg, 0.21 mmol.). After stirring for 10 min., dimethylacetamidedimethyl acetal (0.034 mL, 0.21 mmol.) was added. The reaction was thenstirred at room temperature for 25 min. and then refluxed for 2 h. Aftercooling to room temperature, the reaction was evaporated in vacuo andpartitioned between 5% NaOH and CH₂ Cl₂. The organic phase was thenwashed with saturated NaCl, dried (Na₂ SO₄) and evaporated leaving 100mg of Intermediate (XXXIXb) as a yellow oil (95% yield).

Examples 24B and 24C

To a suspension of 60% NaH (160 mg, 4.0 mmol; washed twice with hexane)in DMF (3 mL) was added a solution of Intermediate (XXXIVb) (100 mg,0.20 mmol.) in DMF (7 mL). After stirring for 35 min., a solution of4-tetrahydro-pyranyloxymethylbenzyl chloride (XXXIVc) (0.53 g, 2.20mmol.) in DMF (2 mL) was added followed by addition of potassium iodide(0.33 g, 2.0 mmol.). After stirring overnight, additional chloride(XXXIVc) (0.53 g, 2.20 mmol.) was added and the reaction was heated to50° C. and stirred overnight. The reaction was quenched by addition ofacetic acid (1 mL) in Et₂ O (100 mL). After basification with 5% NaOH,the organic phase was washed with water (2×), brine (2×), dried (Na₂SO₄), and evaporated leaving 2.1 g of a yellow oil. This material wastaken up in methanol (10 mL) and 4N HCl in dioxane (5 mL) was added.After stirring overnight, the reaction was evaporated in vacuo andpartitioned between 5% NaOH and CH₂ Cl₂. The organic phase was dried andevaporated leaving 1.1 g of an orange oil. Column chromatography (flashsilica gel; 5% MeOH/CH₂ Cl₂ and 0.1% NH₄ OH) gave 182 mg of Example 24Band 300 mg of Example 24C, both as white solids.

Example 24B: Mass spec. MH⁺ =445.2; mp=105°-110° C. (HCl salt)

Example 24C: Mass spec. M⁺ =565.5; mp=72°-75° C. (Note: The mass spec isM⁺ since this is already a charged species.)

Example 24A

By an analogous process reported above, and instead using benzylchloride, the desired product was obtained. The acid deprotection stepwas not performed in this instance.

Example 24A: ¹ H NMR (300 MHz, CDCl₃): δ 6.90-7.35 (m, 15 H), 4.09-4.14(m, 2 H), 3.56 (dd, 2 H), 3.13 (dd, 1 H), 2.50-2.95 (m, 5 H), 1.97 (s, 3H). Mass spec. MH⁺ =415.1, mp=130°-137° C.

                                      TABLE 2n                                    __________________________________________________________________________     ##STR92##                                                                                                        MS                                        Ex No                                                                             R.sup.22   R.sup.23   R.sup.4 = R.sup.7                                                                 R.sup.5 = R.sup.6                                                                 K.sub.i                                                                         (M + H).sup.+                             __________________________________________________________________________    24A . .        benzyl     benzyl                                                                            OMEM  415.1                                     24B HCl        m-(HO)C.sub.6 H.sub.4 CH.sub.2                                                           benzyl                                                                            OH    445.2                                     24C m-(HO)C.sub.6 H.sub.4 CH.sub.2                                                           m-(HO)C.sub.6 H.sub.4 CH.sub.2                                                           benzyl                                                                            OH    (565.2)                                   __________________________________________________________________________

The structures of the Examples below are shown in Table 2o.

Example 25A

Intermediate (XLVa), (3S,5R)-5- (1'R)-1'-(t-Butyloxycarbonyl)amino!-2'-phenethyl!-3-phenylmethyltetrahydrofuran-2-one,can be prepared from N-Boc-phenylalanine following the 8-step procedureof G. B. Dreyer, et al Biochem. 1992, 31, 6646-6659!. This is convertedto the acid (XLVb) using the procedure of B. E. Evans, et al J. Org.Chem. 1985, 50, 4615-4625!, wherein a solution of (3S,5R)-5- (1'R)-1'-(t-Butyloxycarbonyl)amino!-2'-phenethyl!-3-phenylmethyltetrahydrofuran-2-one(XLVa) (11.0 g, 2.5 mmol) in 15 mL of dioxane/7.5 mL of water wastreated with 2.7 mL of 1N NaOH dropwise. The mixture was stirred at roomtemperature for 30 min. and then concentrated at rt on a rotaryevaporator. The residue was acidified with 10% citric acid and extractedinto ether. The ether extract was washed with water, brine and driedover MgSO₄. The solution was filtered and concentrated to give thehydroxy acid as white solid.

The hydroxy acid was immediately dissolved in dry DMF and treated witht-butyldimethylsilyl chloride (2.6 g, 17.5 mmol) and imidazole (2.2 g).The mixture was stirred overnight at room temperature. Analysis by TLC(50:50 EtOAc/Hex) showed no starting material remained, at which timethe solution was concentrated in vacuo and the residue acidified to pH 4with 10% citric acid and extracted into ether. The ether extract waswashed with water, brine and dried over MgSO₄. The solution was filteredand concentrated to give 1.7 g of the silyl ether-silyl ester as acolorless syrup.

A solution of the silyl ether-silyl ester in tetrahydrofuran (THF, 10mL) was treated with 10 mL of glacial acid and water (3 mL). Thesolution was stirred at room temperature for 2.5 hrs until analysis byTLC showed complete conversion to silyl ether-acid (XLVb). The solutionwas concentrated in vacuo and the resulting residue diluted with waterand extracted into ether. The ether extract was washed with water, brineand dried over MgSO₄. The solution was filtered and concentrated to givethe acid (XLVb) as a solid.

A solution of the acid (XLVb) in dioxane was treated with N-hydroxysuccinimide (290 mg, 2.5 mmol) and 1,3-dicyclohexylcarbodiimide (DCC,500 mg, 2.5 mmol) and stirred overnight. The solution was cooled in anice bath and the solids were filtered off. The filtrate was concentratedto give the activated ester (XLVc) as a sticky foam. MS (M+H)+=625.5(41%); (M+H-BOC)+=525.4 (100%).

The above activated ester (XLVc) was dissolved in ether, cooled in anice bath and treated with HCl(g) for 15 minutes and stirred at 0° C. foran additional hour. The solution was concentrated in vacuo at RT to givea white foam. This was dissolved in THF (100 mL) and made basic withtriethyamine (3 mL). The resulting suspension was stirred at roomtemperature overnight. The solution was concentrated and the residue waschromatographed on silica gel (medium pressure LC, ethyl acetate). Thiswas further purified by HPLC chromatography on silica gel (50:50EtOAc/Hex) to give 170 mg (17% overall yield/6 steps) of the lactam(XLVd) as a colorless oil. MS (M+H)+=410.2 (100%)

A solution of (XLVd) (170 mg, 0.42 mmol) in DMF was cooled to 0° C. andtreated with 60% NaH in oil dispersion (25 mg, 0.62 mmol) and stirred at0° C. for 30 minutes. Benzyl bromide (105 mg, 0.44 mmol) was added andstirred for 1 hour and the reaction was allowed to warm to roomtemperature. The mixture was cooled to 0° C. and quenched with 1N HCland diluted with water. The suspension was extracted into ethyl acetate,washed with water, brine, dried over MgSO₄ and concentrated. The residuewas HPLC chromatographed on silica gel (30% EtOAc/Hex) to give 130 mg of(XLVf) as a colorless film. MS (M+H)+=500.2 (100%).

The silyl ether-lactam (XLVf) (130 mg, 0.26 mmol) was dissolved intetrabutylammonium fluoride (TBAF, 1M in THF, 5 mL) solution and stirredat room temperature for 30 minutes. The solution was diluted with waterand extracted into ethyl acetate. The extracts were washed with water,brine, dried over MgSO4 and concentrated. The residue was HPLCchromatographed on silica gel (65% EtOAc/Hex) to give 79 mg of Example25A (XLVg) as a white foam. MS (M+H)+=386.2 (100%).

                  TABLE 2o                                                        ______________________________________                                         ##STR93##                                                                                                          MS                                      Ex No   R.sup.22  R.sup.23                                                                              R.sup.4 K.sub.i                                                                           (M + H).sup.+                           ______________________________________                                        25A     benzyl    benzyl  benzyl  +   386.2                                   ______________________________________                                    

The structures of the Examples below are shown in Table 2p.

Example 26A 5H-dibenzo A,D! cyclohepten-5-one-10,11-dihydro-10,11-diol

A mixture of 5H-dibenzo A,D!cyclohepten-5-one-10,11-dihydro-10,11-diolacetate (ester) (100 mg, 0.31mmol) and sodium hydroxide 50% aqueous solution (5 drops) was dissolvedin methanol (10 ml). The mixture was stirred at room temperature for 5minutes, neutralized with concentrated hydrochloric acid and extractedwith ethyl acetate twice. The organic layer was washed with water,brine, dried with magnesium sulfate and then concentrated in vacuo. Theconcentrate was dissolved with a minimum amount of methylene chlorideand hexane was added to the cloudy point. The resulting precipitate wasfiltered to give opaque fine needle crystals (47 mg, 64%). mp107.5°-107.9° C., Mass Spec 241.1 (M+H)⁺ ; Analysis Calc. for C₁₅ H₁₂ O₃: C, 74.99; H, 5.03; Found: C, 74.70; H, 5.01. ¹ H NMR (CDCl₃ /TMS) δ7.85(2H, m), 7.67(2H, m), 7.57(2H, m), 7.44(2H, m), 5.02(2H, m),3.03(2H, m).

                  TABLE 2p                                                        ______________________________________                                         ##STR94##                                                                                                            MS                                    Ex No  R.sup.22 - R.sup.4                                                                      R.sup.23 - R.sup.7                                                                      K.sub.i                                                                           mp, °C.                                                                         (M + H).sup.+                         ______________________________________                                        26A    fused     fused     +   107.5-108                                                                              241                                          aromatic  aromatic                                                     ______________________________________                                    

The structures of the Examples below are shown in Table 2q.

Example 27A

Compound XXIIb (3.0 g, 4.8 mmol) was dissolved in of anhydrousacetonitrile (40 ml) and to this solution was added benzyl bromide (820mg) and tetrabutylammonium iodide (20 mg). The contents were heated atreflux under a nitrogen atmosphere for 14 h and the solvent was removedunder reduced pressure. The crude residue was chromatographed on silicagel using ethyl acetate-hexane (1:1) as the eluent. The major fractioncontained 2.5 g (76% yield) of Intermediate (LIIIa) as a white solid.

MS: (M+H)⁺ 699.4, (100%); ¹ H NMR (CDCl₃): δ 7.25 (m, 12 H), 6.99 (m,3H), 4.95 (d, ¹ H), 4.82 (d, 1H), 4.65 (d, 1H), 4.50 (d, 1H), 4.15 (m,1H), 3.85 (m, 1H), 3.62 (m, 1H), 3.60 (m, ¹ H), 3.56 (m, 1H), 3.4 (s,3H), 3.39 (m, 1H), 3.35 (s, 3H), 3.12 (m, 1H), 2.92 (m, 1H), 2.10 (s,3H).

Intermediate (LIIIa) (300 mg, 0.48 mmol) was dissolved in methanol (5ml) and a solution of hydrochloric acid in dioxane (4M, 5 ml) was added.This mixture was stirred at room temperature for 4 h and then thesolvent was removed under reduced pressure (the excess HCl can beremoved by extensive washing with methanol followed by evaporation). Thecrude residue was chromatographed on silica gel using a 10% ethylacetate in methylene chloride as the eluent. The major product contained175 mg (81%) of Example 27A. mp: 91°-93° C. MS: (M+H)⁺ 523.2, (100%). IR(KBr, cm⁻¹): 3416, 3086, 1584 and 1282. ¹ H NMR (CDCl₃): δ 7.25 (m, 10H), 5.85 (d, 1H), 3.80 (m, 1H), 3.65 (d, 1H), 3.38 (s, 1H), 3.12-2.90(m. 2H), 2.21 (s, 1H). ¹³ C NMR (CDCl₃, ppm) 193.6, 139.9, 137.6, 130.2,130.1, 129.1, 128.8, 128.3, 127.0, 72.0, 67.7, 62.2, 32.8.

The above reaction (removal of the MEM protecting group) can also bedone by dissolving the starting material in methanol followed bybubbling HCl gas into the solution for 5 min at -10° C. and thenstirring at room temperature for 20 min. Similar work up of the firstprocedure leads to the desired Example 27A.

Example 27B

By substituting cyclopropylmethyl bromide into procedure of Example 27Aand using the appropriate mono-alkylated cyclic thiourea, Example 27Bwas prepared in good yield. mp: 84°-86° C.; MS: (M+H)⁺ 451.1; ¹ H NMR(CDCl₃): δ 7.35-7.20 (m, 5H), 5.0 (d, 1H), 4.85 (d, ¹ H) 4.10 (m, 2H),3.95 (m, 1H), 3.75 (m, 1H), 3.45 (m, 2H), 3.38 (s, 3H), 3.2 (m, 1H), 3.0(m, 1H), 2.78 (m, 1H), 1.20 (m, 1H), 0.21 (m,2H), 0.17 (m, 2H)

Example 27C

Using an analogous procedure to that described for Example 27B, Example27C was prepared in good yield. mp: 257°-259° C.; MS: (M+H)⁺ 583.2; ¹ HNMR (CDCl₃): δ 7.25-7.15 (m, 9H), 5.80 (m, 2H), 4.75 (s, 2H), 3.82 (m,1H), 3.42 (m, 1H), 3,35 (m, 2H), 2.95 (m,2H).

Example 27D

Using an analogous procedure to that described for Example 27A, Example27D was prepared in good yield (m-MEMOCH₂ C₆ H₅ CH₂ Br was thealkylating agent). mp: 253°-255° C.; MS(CDI): m/e 583.3 (100%, M+H); ¹ HNMR (CD₃ OD, 300 MHz) δ 2.95 (m, 2H), 3.20 (m, 1H), 3.40 (m, 1H), 3.78(m. 1H), 5.82 (m, 1H) and 7.15-7.30 (m, 9H).

Example 27E

By using the appropriate alkylating agent (m-cyanobenzylbromide),Example 27E was prepared in an anologous procedure to Example 27A; mp:154°-155° C.; MS(CDI): m/e 548.2 (100%, M+H); ¹ H NMR (CD₃ OD, 300 MHz)δ 2.81 (m, 1H), 2.95 (m, 2H), 3.20 (m, 1H), 3.25 (m, 2H), 3.85 (m, 1H),3.90 (m, 1H), 5.25 (m, 1H), 5.80 (m, 1H), 7.10 (m, 5H), 7.15 (m, 10H)and 7.25 (m, 4H).

Example 27F

Example 27F was made by using p-MEMOC₆ H₅ CH₂ Br as the alkylating agentin the procedure of Example 27A. mp: 162° C.; MS (CDI): m/e 555.2 (100%,M+H); ¹ H NMR (CD₃ OD) δ 2.85 (m, 2H), 3.12 (m, 2H), 3.8 (m, 1H), 5.80(m, 1H), 6.75 (m, 2H), 6.95 (m, 2H) and 7.15 (m, 5H).

Example 27G

Example 27G was prepared according to the procedure described forExample 27A, using m-MEMOC₆ H₅ CH₂ Br as the alkylating agent. mp: 82°C.; MS (CDI): m/e 583.2 (100%, M+H); ¹ H NMR (CD₃ OD, 300 MHz) δ 2.85(m,2H), 3.25 (m, 2H), 3.62 (s, 3H), 3.90 (m, 1H), 5.80 (m, 1H), 6.80 (m,3H) and 7.10-7.20 (m, 6H).

Example 27H

Example 27H was prepared using an analogous procedure to that describedfor Example 27A by employing m-NCC₆ H₅ CH₂ Br as the alkylating agent.mp: 110° C.; MS(CDI): m/e 577.2 (M+H); ¹ H NMR (CD₃ OD, 300 MHz) δ 2.8(m, 2H), 3.15 (m, 2H), 3.45 (m,2H), 3.65 (m, 1H), 3.70 (m, 1H), 3.82 (m,1H), 4.15 (m, 1H), 5.28 (m, 1H), 5.82 (m, 1H), 7.25 (m, 4H), 7.40 (m, 10H) and 7.80 (m, 4H).

Example 27I

Example 27K was prepared by treating Example 27H with hydroxylamine.HCl,using an analogous procedure to that described for Example 27N. mp:130°-132° C.; MS (CDI): m/e 611.2 (100%, M+H); ¹ H NMR (CD₃ OD, 300 MHz)δ 2.81 (m, 2H), 3.21 (m, 2H), 3.45 (m, 2H), 3.8 (m, 2H), 4.72 (m, 2H),5.85 (m, 2H) and 7.25 (m, 18 H).

Example 27J

Example 27L was synthesized in a similar fashion to that described forExample 27F by using m-MEMOC₆ H₅ CH₂ Br as the alkylating agent. mp:125° C.; MS(CDI): m/e 555.3 (100%, M+H); ¹ H NMR (CD₃ OD, 300 MHz) δ3.05-3.20 (m, 2H), 3.41-3.60 (m, 2H), 3.95 (m, 1H), 5.82 (m, 1H), 6.80(m, 3H) and 7.20 -7.45 (m, 6H).

Example 27K

Example 27M was prepared using an analogous procedure to that describedfor Example 27A by using m-NCC₆ H₅ CH₂ Br as the alkylating agent. mp:102° C.; MS(CDI): m/e 573.3 (100%, M+H); ¹ H NMR (CD₃ OD, 300 MHz) δ2.80 (m, 1H), 3.05 (m, ¹ H), 3.20 (m, 1H), 3.42 (m, 1H), 3.78 (m, 1H),5.15 (m, 1H), 7.15 (m, 2H), 7.25 (m, 3H), 7.45 (m, 1H) and 7.60 (m, 3H).

Example 27L

To a solution containing 200 mg (0.34 mmol) of Example 27M in 10 mL ofanhydrous ethanol was added 60 mg (0.87 mmol) of hydroxylamine.HCl and87 mg (0.87 mmol) of triethylamine. The reaction mixture was heated atreflux until the starting material could not be detected by TLC), andthen the solvent was removed under reduced pressure. The residue waschromatographed on a C₁₈ silica column using a 20% solution of water inmethanol as the eluent. The major fraction isolated contained 97 mg (45%yield) of thiourea, Example 27N. mp: 150° C.; MS(DCI): m/e 639.2 (100%,M+H); ¹ H NMR (CD₃ OD, 300 MHz) δ 2.85 (m, 2H), 3.15 (m, 1H), 3.25 (m,1H), 3.80 (m, 1H), 5.82 (m, 1H), 7.15 (m, 5H) and 7.45 (m, 4H).

Example 27M

To a solution of containing 5.0 g (10.5 mmol) of Di-amine-Di-MEMcompound III in 75 ml of THF was added 2.20 g (22.0 mmol) of K₂ CO₃ and4.48 g (23.0 mmol) of 4-fluoro-3-cyanobenzyl bromide. The reactionmixture was stirred at room temperature for 18 h and then 100 mL ofwater was added. The mixture was extracted with CH₂ Cl₂ and the organiclayer was dried over MgSO₄ and filtered. The filtrate was treated with1.73 g (15.0 mmol) of thiophosgene and 2.0 g (20.0 mmol) oftriethylamine. The reaction was stirred at room temperature overnightand then washed with 100 mL of 10% citric acid. The organic layer waswashed with brine, dried over MgSO₄ and filtered. The solvent wasremoved under reduced pressure and the residue was chromatographed onsilica gel using a 50% solution of ethyl acetate in hexane as the eluentto give 2.45 g (30% yield ) of the alkylated intermedicate. Removal ofthe the MEM groups was done by using analogous procedure to thatdescribed for intermediate LIIIa . The thiourea compound obtained fromthe previous step was converted to example 27P by applying the sameporcedure described for Example 27N. mp 154° C.; MS(DCI): m/e 675.2(100%, M+H); ¹ H NMR (CD₃ OD, 300 MHz) 2.85 (m, 2H), 3.35 (m, 1H), 3.52(m, 1H), 3.78 (m, 1H), 5.61 (m, 1H), 7.10 (m, 1H) and 7.25 (m, 8H).

                                      TABLE 2q                                    __________________________________________________________________________     ##STR95##                                                                        Stereo              HPLC        Mass Spec                                 Ex. No                                                                            2.3.4.5                                                                           R.sup.22 = R.sup.23                                                                   R.sup.4 = R.sup.7                                                                     K.sub.i                                                                           IC.sub.90                                                                        mp, °C.                                                                     (m + H)                                   __________________________________________________________________________    27A RSSR                                                                              C.sub.6 H.sub.5 CH.sub.2                                                              C.sub.6 H.sub.5 CH.sub.2                                                              +++ +++                                                                              92-94                                                                              523.2                                     27B RSSR                                                                              (C.sub.3 H.sub.5)CH.sub.2                                                             C.sub.6 H.sub.5 CH.sub.2                                                              +++ +++                                                                              84-86                                                                              451.1                                     27C RSSR                                                                              p-HOC.sub.6 H.sub.4 CH.sub.2                                                          C.sub.6 H.sub.5 CH.sub.2                                                              +++ +++                                                                              257-258                                                                            583.2                                     27D RSSR                                                                              m-HOCH.sub.2                                                                          m-HOCH.sub.2                                                                          +++ +++                                                                              253-355                                                                            563.3                                             C.sub.6 H.sub.4 CH.sub.2                                                              C.sub.6 H.sub.4 CH.sub.2                                      27E RSSR                                                                              m-cyano-                                                                              C.sub.6 H.sub.4 CH.sub.2                                                              +++ +++                                                                              154-155                                                                            548.2                                             C.sub.6 H.sub.4 CH.sub.2                                              27F RSSR                                                                              p-HOC.sub.6 H.sub.4 CH.sub.2                                                          p-HO    +++ +++                                                                              162  555.2                                                     C.sub.6 H.sub.4 CH.sub.2                                      27G RSSR                                                                              m-CH.sub.3 O                                                                          m-CH3O  +++ +++                                                                              82   583.2                                             C.sub.6 H.sub.4 CH.sub.2                                                              C.sub.6 H.sub.4 CH.sub.2                                      27H RSSR                                                                              m-cyano-                                                                              p-HOCH.sub.2                                                                          +++ +++                                                                              110  577.2                                             C.sub.6 H.sub.4 CH.sub.2                                                              C.sub.6 H.sub.4 CH.sub.2                                      27I RSSR                                                                              m-HONNH2                                                                              p-HOCH.sub.2                                                                          +++ +++                                                                              130-132                                                                            611.2                                             C.sub.6 H.sub.4 CH.sub.2                                                              C.sub.6 H.sub.4 CH.sub.2                                      27J RSSR                                                                              m-HO    m-HO    +++ +++                                                                              125  555.3                                             C.sub.6 H.sub.4 CH.sub.2                                                              C.sub.6 H.sub.4 CH.sub.2                                      27K RSSR                                                                              m-cyano-                                                                              m-cyano-                                                                              +++ +++                                                                              102  573.3                                             C.sub.6 H.sub.4 CH.sub.2                                                              C.sub.6 H.sub.4 CH.sub.2                                      27L RSSR                                                                              m-      m-      +++ +++                                                                              150  639.2                                             (H.sub.2 NC(NOH))                                                                     (H.sub.2 NC(NOH))                                                     C.sub.6 H.sub.4 CH.sub.2                                                              C.sub.6 H.sub.4 CH.sub.2                                      27M RSSR                                                                              m-      m-      +++ +++                                                                              152-153                                                                            675.2                                             (H.sub.2 NC(NOH))                                                                     (H.sub.2 NC(NOH))                                             p-fluoro-                                                                     p-fluoro-                                                                             C.sub.6 H.sub.4 CH.sub.2                                                              C.sub.6 H.sub.4 CH.sub.2                                      __________________________________________________________________________

The structures of the Examples below are shown in Table 2r. Compounds inTable 2r were prepared as shown in Scheme 28.

Example 28D

Preparation of Diamine (La):

To a suspension of 10 g of(2R,3S,4S,5R)-2,5-bis-(N--Cbz-amino)-3,4-(dihydroxy)-1,6-diphenylhexanein 200 mL of methylene chloride was added 10.8 mL of2,2-dimethoxypropane and 0.41 g of camphorsulfonic acid. The mixture wasstirred at room temperature for 48 hr, then washed successively withsaturated sodium hydrogen carbonate solution and saturated sodiumchloride solution. The organic phase was dried over anhydrous magnesiumsulfate and concentrated on a rotary evaporator. The residue wascrystallized from ether/hexane (1/10 v/v) to give 6.6 g (60% yield)acetonide as white needles, mp 76°-77° C.

To a solution of 6.6 g of this acetonide in 100 mL oftetrahydrofuran/ethanol (1/1 v/v) was added 0.7 g of 10% Pd/C. Themixture was stirred vigorously under 1 atmosphere of hydrogen gas for 18hr. The catalyst was isolated by filtration and washed withtetrahydrofuran. The combined filtrate and washings were concentrated ona rotary evaporator. The residue consisted of 3.6 g (100% yield) ofdiamine, La, which was used without further purification.

To a solution of 2 g of compound La in 15 mL of anhydroustetrahydrofuran, maintained at 0°-10° C. under a nitrogen atmospherewith efficient stirring, was added 1.8 mL (2.2 eq) of triethylaminefollowed by dropwise addition of a solution of 0.9 mL (1 eq) ofphenyldichlorophosphate in 4 mL of tetrahydrofuran. The mixture wasstirred for 16 hr at room temperature. The resulting triethylaminehydrochloride was isolated by filtration and washed withtetrahydrofuran. The combined filtrate and washings were concentrated ona rotary evaporator, taken up in methylene chloride/ethyl ether (1/1v/v), and washed successively with water (2×), and saturated sodiumchloride solution (1×). After drying over anhydrous magnesium sulfate,the organic layer was concentrated on a rotary evaporator. Purificationof the residue by column chromatography using a short pad of silica geleluting with hexane/ethyl acetate (1/1 v/v) gave 1.8 g (64% yield) ofthe cyclic phosphoramide, Lb, as a sticky white foam.

To a solution of 0.1 g of compound Lb in 3 mL of anhydrousN,N-dimethylformamide, maintained under a nitrogen atmosphere at roomtemperature, was added 35 mg of 60% NaH (by weight, dispersed in oil).The mixture was stirred for 10-15 min followed by addition of 0.16 mLbromomethylcyclopropane. The mixture was stirred for 48 hr at roomtemperature, then quenched by water addition. The product was extractedwith ethyl acetate (3×). The combined extracts were washed successivelywith water (2×) and saturated sodium chloride solution (1×), dried overanhydrous magnesium sulfate, and concentrated on a rotary evaporator.The residue was purified using rotary preparative tlc eluting withhexane/ethyl acetate (4/1 v/v) to give 97 mg (79% yield) of thebisalkylated product as an amber oil. To a solution of 97 mg of thisbisalkylated product in 2 mL of anhydrous methylene chloride, maintainedunder an argon atmosphere at -78° C., was added 0.5 mL of a 2.0Msolution of dimethylboron bromide in methylene chloride by dropwiseaddition. The addition was completed in 10-15 min, and the mixture wasthereafter stirred for 1 hr at -78° C. The mixture was then transferredvia syringe to a rapidly stirring mixture of 1 mL tetrahydrofuran and0.5 mL aqueous saturated sodium hydrogen carbonate solution. Afterstirring for 5 min, the mixture was extracted with ethyl acetate (3×).The combined extracts were washed successively with 10% aqueouspotassium hydrogen sulfate solution and saturated sodium chloridesolution. After drying over anhydrous magnesium sulfate, the organiclayer was concentrated by rotary evaporation. The residue was purifiedby rotary preparative tlc eluting with hexane/ethyl acetate (4/1 v/v) togive 70 mg (78% yield) of compound 28D as an amorphous white solid. MS547 (M+H)⁺ 453 (100%, M+H-C₆ H₅ OH)⁺. ¹ H NMR(CDCl₃) δ 0.24 (4H,m) 0.44(4H,m) 0.95 (2H,m) 2.22 (1H,d) 2.52 (1H,m) 3.18 (4H,m) 3.38 (2H,m) 3.63(1H,m) 3.90 (1H,t) 4.03 (2H,m) 7.00 (1H,m) 7.06 (2H,t) 7.24 (10 H,m)7.50 (2H,m)

Example 28M

Compound of example 28M was prepared from compound Lb using thealkylation procedure described for example 28D by replacing thebromomethylcyclopropane with 3-(N-methyl-N-trifluoroacetamido)benzylbromide. A solution of 0.27 g of the bisalkylation product, thusprepared, in 7 mL of methanol was treated with 4 eq of solid potassiumcarbonate. The mixture was stirred for 48 hr at room temperature,diluted with water, and extracted with methylene chloride. The extractwas washed successively with saturated sodium hydrogen carbonatesolution and saturated sodium chloride solution, then dried overanhydrous magnesium sulfate. Concentration by rotary evaporation andpurification of the residue by column chromatography using silica geleluting with hexane/ethyl acetate (1/1 v/v) gave the free amino compoundin 57% yield.

To a solution of this diamine in 3 mL of methanol was added 0.01 gp-toluenesulfonic acid monohydrate. The solution was stirred for 1 hr atroom temperature, then concentrated by rotary evaporation. The residuewas taken up in ethyl acetate, washed with saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate.Concentration by rotary evaporation and purification by columnchromatography on silica gel using methylene chloride/ethylacetate/ethanol (10/10/0.5 volume ratios) gave a 19% yield of compound28M. MS: 583 (M+H-C₆ H₅ OH) ¹ H NMR (CDCl₃): δ 2.58-2.77 (m, 2H); 2.70(s, 3H): 2.78 (s, 3H); 3.02 (d, 2H); 3.20-3.39 (m, 2H); 3.42 (d of d,2H); 3.50-3.73 (m, 2H); 3.88 (s, 2H); 4.30-4.59 (m, 4H); 6.42-6.52 (m,4H); 6.55-6.62 (m, 3H); 6.95 (d, 2H); 7.00-7.37 (m, 10 H); 7.52 (d, 2H).

                                      TABLE 2r                                    __________________________________________________________________________     ##STR96##                                                                    Ex.                K.sub.i     Mass Spec                                      No.                                                                              R.sup.22 = R.sup.23                                                                  R.sup.4 = R.sup.7                                                                 R.sup.24A                                                                          HPLC                                                                              IC.sub.90                                                                        mp, °C.                                                                     (M + H)                                        __________________________________________________________________________    28A                                                                              H      benzyl                                                                            phenyloxy                                                                          +   ++      456                                                                           (M + NH.sub.4)                                 28B                                                                              2-naphthyl                                                                           benzyl                                                                            phenyloxy                                                                          ++  +++                                                       methyl                                                                     28C                                                                              cyclopropyl                                                                          benzyl                                                                            phenyloxy                                                                          ++  +++     547                                               methyl                                                                     28D                                                                              n-butyl                                                                              benzyl                                                                            phenyloxy                                                                          ++  +++     551                                            28E                                                                              4-(HOCH.sub.2)-                                                                      benzyl                                                                            phenyloxy                                                                          ++  +++                                                       benzyl                                                                     28F                                                                              H      benzyl                                                                            ethoxy                                                                             +   ++/+                                                                             245-246                                                                            408                                                                           (M + NH.sub.4)                                                                391                                            28G                                                                              cyclopropyl                                                                          benzyl                                                                            dimethyl                                                                           +   ++      498                                               methyl     amino                                                           28H                                                                              4-(HOCH.sub.2)-                                                                      benzyl                                                                            methoxy                                                                            ++  ++      617                                               benzyl                                                                     28I                                                                              4-(HOCH.sub.2)-                                                                      benzyl                                                                            dimethyl                                                                           ++  ++ 159-160                                                                            630                                               benzyl     amino                                                           28J                                                                              3-(HOCH.sub.2)-                                                                      benzyl                                                                            phenoxy                                                                            ++  ++ 109-110                                                benzyl                                                                     28K                                                                              benzyl benzyl                                                                            methyl                                                                             ++          541                                            __________________________________________________________________________

The examples below are representative procedures for the preparation ofthe compounds shown in Table 2s below.

Example 29A

Compound of example 5U (11.340 g, 20 mmol) was dissolved in 60 mltetrahydrofuran and cooled to 0° C.di-t-butyl-N,N-diethylphosphoramidite 13.000 g(52 mmol) in 40 mltetrahydrofuran was added followed by addition of 7.28 g(104 mmol) oftetrazole. The contents were stirred for 5 minutes in the 0° C. ice bathand then for 15 minutes in a water bath at approximately 23° C. Thecontents were cooled in a -40° C. bath and 21.5 g(62.4 mmol) of 50%m-chloroperoxybenzoic acid in 100 ml dichloromethane added over a 10minute period and stirred for 5 minutes in the same bath and then 15minutes in a water bath at approximately 23° C. The reaction wasquenched with 250 ml of 10% aqueous sodium bisulfite at 0° C. Theaqueous layer was extracted with ether (100 ml). The organic extractswere combined and washed with sat. sodium bicarbonate (100 ml), 10%aqueous sodium bisulfite (250 ml) and then sat. sodium bicarbonate (100ml). The organic layer was separated and dried over magnesium sulfateand the filtrate taken to dryness. The residue was purified on SiO₂ gel750 g; using chloroform (500 ml) followed by 1% Methanol:Chloroform (4liters) followed by 1.5% (4 liters)! to provide 14.410 g (75.8% yield)of the bisphosphate ester as a white solid. Caution| The "flashchromatography" column should be done as fast as possible to avoid anydecomposition on the column support. ¹ H NMR(300 MHz)(CDCl₃) δ1.441(36H,d,J=4 Hz), 2.974(6H,m), 3.353 (2H,s), 3.49(4H,m),4.865(2H,d,J=8 Hz), 4.919 (4H, d, J=14 Hz), 7.111(10H,t,J=8 Hz),7.293(8H,m); ³¹ P NMR(121 MHz) (CDCl₃) δ -9.8 (s,decoupled).

This diester intermediate (36 g, 37.85 mmol) was dissolved in 200 mlmethanol and to this solution was added 3.6 g of Amberlyst 15 ionexchange resin. The contents were stirred at reflux for 5 hours. Themixture was filtered through a celite pad and concentrated to afford 27g (98.2%) of Compound 29A as a white solid. ¹ H NMR (DMSO-d₆) δ2.842(4H,m), 2.955 (2H,m), 3.336(2H,s), 3.420(2H,d,J=11 Hz),4.662(2H,d,J=4.2 Hz), 4.822(4H,d,J=6.9 Hz), 7.016(4H,d,J=6.9 Hz),7.084(4H,d,J=7.7 Hz), 7.266(10H,m); ³¹ P NMR (DMSO-d₆) δ-0.48(s,decoupled)

Example 29B

Compound 29A (2.178 g, 3 mmol) was treatd slowly with 11.71 ml (12 mmol)of 1.024N Potassium bicarbonate solution. After the addition wascomplete the solution was filtered through a sintered glass filterfunnel and lyophilized to afford 2.433 g (92.3% yield) of desiredtetrapotassium salt as a white solid.

Example 29D

Compound 5U (8.2 g, 14.4 mmol) was dissolved in methylene chloride (170ml) under a nitrogen atmosphere. N,N-Dimethylglycine (1.78 g, 17.3 mmol,1.2 equiv.) was added followed by the reagents,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.32 g,17.3 mmol, 1.2 equiv.) and 4-dimethylaminopyridine (2.11 g, 17.3 mmol,1.2 equiv.). After stirring overnight, silica gel (40 g, 230-400 mesh)was added and the solvent removed on a rotary evaporator. The residuewas applied to the top of flash silica gel column and eluted with 20%methanol-80% ether to give partially purified D. Further chromatographyusing 15% isopropanol-85% methylene chloride gave the desired monoester(2.54 g, 27%). ¹ H NMR (300 MHz, CDCl₃) δ 7.35-7.02(18H, m), 5.06(2H,s), 4.85(1H, d), 4.80(1H, d), 4.50(2H, s), 3.46(6H, m), 3.07(2H, s),2.96(7H, m), 2.22(6H, s). ¹³ C NMR (75.4 MHz, CDCl₃) δ 170.2, 162.1,140.2, 139.6, 138.4, 137.3, 134.8, 129.5, 129.4, 128.9, 128.5, 128.5,128.1, 127.1, 126.4, 71.1, 71.0, 66.0, 64.3, 63.8, 60.1, 55.3, 55.1,45.1, 32.6.

This mono-ester (1.39 g, 2.14 mmol) was dissolved in a mixed solventsystem (88 ml, 9% isopropanol-91% ether). A solution of hydrochloricacid (0.59 ml, 2.35 mmol, 1.1 equiv., 4.0M in dioxane) was addeddropwise. After stirring for 1.5 hours, the reaction was filtered undernitrogen. The filtrate was rinsed into a flask with water and frozen.The frozen solution was lyophilized to give 29D as itsmono-hydrochloride-monohydrate (1.39 g, 92% for the monohydrate). ¹ HNMR (300 MHz, CD₃ OD) δ 7.38-7.01(18H, m), 5.26(2H, s), 4.82(1H, d),4.78(1H, d), 4.56(2H, s), 4.12(2H, dd), 3.58(4H, m), 3.09-2.78(6H, m),2.91(6H, s). ¹³ C NMR (100.6 MHz, CD₃ OD) δ 166.89, 163.83, 142.37,141.30, 141.24, 140.17, 138.14, 135.64, 130.86, 130.65, 130.48, 129.93,129.67, 129.57, 128.24, 127.48, 72.05, 71.90, 68.81, 67.81, 66.93,64.79, 57.99, 57.07, 56.72, 44.49, 33.64, 33.58. MS (NH₃ CI) m/e652(M+H-HCl).

Example 29E

Compound 5U (5.0 g, 8.82 mmol) was dissolved in methylene chloride (50ml) under a nitrogen atmosphere. An excess of 2,2-dimethoxypropane (10ml) and a catalytic amount of p-toluenesulfonic acid monohydrate (250mg) were then added. After stirring for one hour, water (25 ml) wasadded and stirring continued for ten minutes. The reaction was thentransferred to a separatory funnel where the layers were separated. Theorganic phase was was successively with a saturated aqueous solution ofsodium bicarbonate and brine. After drying over anhydrous magnesiumsulfate, the crude product was isolated by filtration and evaporation.Purification was accomplished by flash silica gel column chromatography(5% methanol-95% methylene chloride). The acetonide was obtained in 90%yield (4.75 g). ¹ H NMR (300 MHz, CDCl₃) δ 7.37-7.23(10H, m), 7.09(8H,d), 4.88(2H, d), 4.65(4H, d), 3.82(2H, s), 3.76(2H, b), 3.04(2H, d),2.92(4H, m), 1.94(2H, t), 1.34(6H, s). ¹³ C NMR (75.4 MHz, CDCl₃) δ161.7, 140.2, 138.8, 137.6, 129.4, 129.3, 129.2, 128.7, 127.2, 126.6,110.2, 75.5, 65.0, 60.8, 56.0, 33.5, 26.7.

This acetonide (999 mg, 1.67 mmol) was dissolved in methylene chloride(10.0 ml) under a nitrogen atmosphere. N,N-Dimethylglycine (431 mg, 4.18mmol, 2.5 equiv.) and the reagents1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (802 mg,4.18 mmol, 2.5 equiv.) and 4-dimethylaminopyridine (511 mg, 4.18 mmol,2.5 equiv.) were added and stirring continued overnight. The reactionwas applied directly to a flash silica gel column and eluted with 10%methanol-90% ether. The desired bis-ester was obtained in 73% yield(0.95 g). ¹ H NMR (300 MHz, CDCl₃) δ 7.36-7.04(18H, m), 5.14(4H, s),4.92(2H, d), 3.86(2H, s), 3.77(2H, d), 3.18(4H, s), 3.08(2H, d),2.92(4H, m), 2.33(12H, s), 1.37(6H, s). MS (NH₃ CI) m/e 777(M+H).

This bis-ester (402 mg, 0.518 mmol) was dissolved in methanol (5.0 ml)and hydrochloric acid (1.0 ml, 1.0N solution) was added. After stirringfor 0.5 hour the solvent was removed by rotary evaporation and theresidue azeotropically dried with toluene. Further drying in vacuo gave29E (383 mg).

                  TABLE 2s                                                        ______________________________________                                         ##STR97##                                                                    Ex.                 K.sub.i             Mass Spec                             No.  R.sup.42 = R.sup.43                                                                          (HPLC)  IC.sub.90                                                                          mp, °C.                                                                       (M + H)                               ______________________________________                                        29A  PO.sub.3 H.sub.2                                                         29B  PO.sub.3.sup.= (K.sup.+)                                                 29C  Me.sub.2 NCH.sub.2 C(O)                                                  29D  R.sup.22 = H, R.sup.23 =           652                                        Me.sub.2 NCH.sub.2 C(O).HCl                                              29E  Me.sub.2 NCH.sub.2 C(O).HCl        737                                   29F  (3-pyridinyl)-                     805                                        CH.sub.2 C(O)                                                            29G  (4-pyridinyl)-                     777                                        CH.sub.2 C(O)                                                            29H  (1-morpholinyl)-                   821                                        CH.sub.2 C(O)                                                            29I  (3-pyridinyl)-                     829                                        CHCHC(O)                                                                 29J  (1-morpholinyl)-                   877                                        (CH.sub.2).sub.3 C(O)                                                    29K  (4-methyl-1-                       903                                        piperazinyl) -                                                                (CH.sub.2).sub.3 C(O)                                                    29L  (1-piperidinyl)-                   837                                        (CH.sub.2).sub.3 C(O)                                                    29M  (4-methyl-1-                       847                                        piperazinyl)-                                                                 CH.sub.2 C(O)                                                            29N  (1-piperidinyl)-                   817                                        CH.sub.2 C(O)                                                            29O  (4-phenyl-1-                       971                                        piperazinyl)-                                                                 CH.sub.2 C(O)                                                            29P  (1-morpholinyl)-                   849                                        (CH.sub.2).sub.2 C(O)                                                    29Q  (CH.sub.3).sub.2 C(NH.sub.2)C(O)   737                                   29R  CH.sub.3 CH(NH.sub.2)C(O)          709                                   29S  3-             +       +++  167-168                                           (1-morpholinyl                                                                methyl) C.sub.6 H.sub.4 C(O)                                                  .HCl                                                                     29T  4-             +       +++  165-167                                           (1-morpholinyl                                                                methyl) C.sub.6 H.sub.4 C(O)                                                  .HCl                                                                     29U  3-(EtNHCH.sub.2)                                                                             +       +++  124-126                                           C.sub.6 H.sub.4 C(O).HCl                                                 29V  4-(EtNHCH.sub.2)                                                                             +       +++  134-136                                           C.sub.6 H.sub.4 C(O).HCl                                                 29W  4-(2-          ++      +++  169-170                                           HOCH.sub.2 CH.sub.2 NHCH.sub.2)                                               C.sub.6 H.sub.4 C(O).HCl                                                 29X  4-(4-methyl-1- ++      +++  224-225                                           piperazinyl                                                                   methyl)-C.sub.6 H.sub.4 C(O)                                                  .2HCl                                                                    29Y  3-(4-methyl-1- ++      +++  195-196                                           piperazinyl                                                                   methyl)-C.sub.6 H.sub.4 C(O)                                                  .2HCl                                                                    ______________________________________                                    

The examples shown in Table 2t were prepared according to Scheme 34.

                  TABLE 2t                                                        ______________________________________                                         ##STR98##                                                                    Ex.                                                                           No.  W       R.sup.22 = R.sup.23                                                                         n   X,Y   K.sub.i                                                                            mp, °C.                      ______________________________________                                        30A  CO      benzyl        1   H,OH  +    52-56                                                              (±)                                         30B  CO      4-(HOCH.sub.2)-benzyl                                                                       1   H,OH  +    70-76                               30C  CO      3-cyanobenzyl 1   H,OH  +    56-65                               30D  CO      4-hydroxybenzyl                                                                             1   H,OH  +    78-85                               30E  CO      cyclopropyl   1   H,OH  +                                                     methyl                                                           30F  CO      2-naphthylmethyl                                                                            1   H,OH  +    59-66                               30G  CO      6-hydroxyhexyl                                                                              1   H,OH  +                                        30H  SO.sub.2                                                                              benzyl        1   H,OH       123-125                             30I  SO.sub.2                                                                              2-naphthylmethyl                                                                            1   H,OH  ++   188.5-                                                                        190                                 30J  SO.sub.2                                                                              cyclopropyl   1   H,OH  +                                                     methyl                                                           30K  SO.sub.2                                                                              4-hydroxymethyl                                                                             1   H,OH  +                                        30L  CO      benzyl        2   H,OH  +    134-136                             30M  CO      2-naphthylmethyl                                                                            2   H,OH  +    179-181                             30N  CO      4-(HOCH.sub.2)-benzyl                                                                       2   H,OH  ++   72-75                               30O  CO      cyclopropyl   2   H,OH  +                                                     methyl                                                           30P  CO      3-cyanobenzyl 2   H,OH  +    142.5-                                                                        144                                 30Q  SO.sub.2                                                                              benzyl        2   H,OH  +    118.120                             30R  CO      3-(H.sub.2 NC(NOH))                                                                         2   H,OH  +++                                                   benzyl                                                           30S  CO      benzyl        2   O     +                                        30T  CO      benzyl        2   NOH   +                                        30U  CO      benzyl        1   H,OH  +                                                                       (R)                                            30V  CO      benzyl        1   H,OH  +                                                                       (S)                                            ______________________________________                                    

The examples in Table 2u were prepared using the procedures outlined inExample 23f above. Compounds where R⁴ =R⁷ =4-fluorobenzyl were preparedfrom(2R,2S,4S,4R)-2,5-bis(N--Cbz-amino)-3,4-dimethoxyethoxymethoxy-1,6-di-(4-fluorophenyl)hexane.Further manipulations to X and Y were carried out using methods wellknown to one of ordinary skill in organic chemistry.

                                      TABLE 2u                                    __________________________________________________________________________     ##STR99##                                                                    Ex. stereo               K.sub.i Mass Spec                                    No. 2,3,4,5                                                                           R.sup.22 = R.sup.23                                                                   R.sup.4 = R.sup.7                                                                 X, Y (HPLC)                                                                             IC.sub.90                                                                        (M + H)                                      __________________________________________________________________________    31A RSSR                                                                              3-carbomethoxy                                                                        4-fluoro                                                                          OH,OH                                                                              ++   +++                                                                              712.4                                                benzyl  benzyl           (M + NH.sub.4)                               31B RSSR                                                                              4-carbomethoxy                                                                        4-fluoro                                                                          OH,OH                                                                              ++   +++                                                                              695.4                                                benzyl  benzyl                                                        31C RSSR                                                                              3-hydroxymethyl                                                                       4-fluoro                                                                          OH,OH                                                                              +++  +++                                                                              639.4                                                benzyl  benzyl                                                        31D RSSR                                                                              4-hydroxymethyl                                                                       4-fluoro                                                                          OH,OH                                                                              +++  +++                                                                              656.2                                                benzyl  benzyl           (M + NH.sub.4)                               31E RSSR                                                                              benzyl  4-fluoro                                                                          OH,H ++   +++                                                                              527.2                                                        benzyl                                                        31F RSRR                                                                              benzyl  benzyl                                                                            epoxy                                                                              +    ++/+                                                                             525.2                                        __________________________________________________________________________

                                      TABLE 13                                    __________________________________________________________________________     ##STR100##                                                                   Ex.                                                                           No.                                                                              R4       R7       R22      R23                                             __________________________________________________________________________    5376                                                                             benzyl   benzyl   2-methallyl                                                                            2-methallyl                                     5377                                                                             1-pyrolylmethyl                                                                        1-pyrolylmethyl                                                                        4-methylpentyl                                                                         4-methylpentyl                                  5378                                                                             1-       1-       3-methallyl                                                                            3-methallyl                                        pyrazolylmethyl                                                                        pyrazolylmethyl                                                   5379                                                                             1-       1-                                                                   imidazolylmethy                                                                        imidazolylmethy                                                                        3-methylbutyl                                                                          3-methylbutyl                                      l        l                                                                 5380                                                                             1-indolylmethyl                                                                        1-indolylmethyl                                                                        3-methylpentyl                                                                         3-methylpentyl                                  5381                                                                             2-pyridylmethyl                                                                        2-pyridylmethyl                                                                        3-pentyl 3-pentyl                                        5382                                                                             3-pyridylmethyl                                                                        3-pyridylmethyl                                                                        4-methylpentyl                                                                         4-methylpentyl                                  5383                                                                             4-pyridylmethyl                                                                        4-pyridylmethyl                                                                        3,3-dimethallyl                                                                        3,3-dimethallyl                                 5384                                                                             cyclohexylmethy                                                                        cyclohexylmethy                                                                        3,3-     3,3-                                               l        l        dimethylbutyl                                                                          dimethylbutyl                                   5385                                                                             2-       2-       allyl    allyl                                              thiophenylmethy                                                                        thiophenylmethy                                                      l        l                                                                 5386                                                                             (3,4-    (3,4-    cyclobutylmethy                                                                        cyclobutylmethy                                    methylenedioxyp                                                                        methylenedioxyp                                                                        l        l                                                  henyl)methyl                                                                           henyl)methyl                                                      5387                                                                             2-thienylmethyl                                                                        2-thienylmethyl                                                                        cyclopropylmeth                                                                        cyclopropylmeth                                                      yl       yl                                              5388                                                                             4-       4-       isobutyl isobutyl                                           biphenylmethyl                                                                         biphenylmethyl                                                    5389                                                                             2-       2-       n-butyl  n-butyl                                            thiomethylethyl                                                                        thiomethylethyl                                                   5390                                                                             p-       p-       n-pentyl n-pentyl                                           hydroxyphenylme                                                                        hydroxyphenylme                                                      thyl     thyl                                                              5391                                                                             p-       p-       propyl   propyl                                             nitrophenylmeth                                                                        nitrophenylmeth                                                      yl       yl                                                                5392                                                                             benzyl   benzyl   2-methallyl                                                                            H                                               5393                                                                             1-pyrolylmethyl                                                                        1-pyrolylmethyl                                                                        4-methylpentyl                                                                         H                                               5394                                                                             1-       1-       3-methallyl                                                                            H                                                  pyrazolylmethyl                                                                        pyrazolylmethyl                                                   5395                                                                             1-       1-       3-methylbutyl                                                                          H                                                  imidazolylmethy                                                                        imidazolylmethy                                                      l        l                                                                 5396                                                                             1-indolylmethyl                                                                        1-indolylmethyl                                                                        3-methylpentyl                                                                         H                                               5397                                                                             2-pyridylmethyl                                                                        2-pyridylmethyl                                                                        3-pentyl H                                               5398                                                                             3-pyridylmethyl                                                                        3-pyridylmethyl                                                                        4-methylpentyl                                                                         H                                               5399                                                                             4-pyridylmethyl                                                                        4-pyridylmethyl                                                                        3,3-dimethallyl                                                                        H                                               5400                                                                             cyclohexylmethy                                                                        cyclohexylmethy                                                                        3,3-     H                                                  l        l        dimethylbutyl                                            5401                                                                             2-       2-       allyl    H                                                  thiophenylmethy                                                                        thiophenylmethy                                                      l        l                                                                 5402                                                                             (3,4-    (3,4-    cyclobutylmethy                                                                        H                                                  methylenedioxyp                                                                        methylenedioxyp                                                                        l                                                           henyl)methyl                                                                           henyl)methyl                                                      5403                                                                             2-thienylmethyl                                                                        2-thienylmethyl                                                                        cyclopropylmeth                                                                        H                                                                    yl                                                       5404                                                                             4-       4-       isobutyl H                                                  biphenylmethyl                                                                         biphenylmethyl                                                    5405                                                                             2-       2-       n-butyl                                                     thiomethylethyl                                                                        thiomethylethyl                                                   5406                                                                             p-       p-       n-pentyl H                                                  hydroxyphenylme                                                                        hydroxyphenylme                                                      thyl     thyl                                                              5407                                                                             p-       p-       propyl   H                                                  nitrophenylmeth                                                                        nitrophenylmeth                                                      yl       yl                                                                5408                                                                             benzyl   p-       2-methallyl                                                                            2-methallyl                                                 nitrophenylmeth                                                               yl                                                                5409                                                                             1-pyrolylmethyl                                                                        benzyl   4-methylpentyl                                                                         4-methylpentyl                                  5410                                                                             1-       1-pyrolylmethyl                                                                        3-methallyl                                                                            3-methallyl                                        pyrazolylmethyl                                                            5411                                                                             1-       1-       3-methylbutyl                                                                          3-methylbutyl                                      imidazolylmethy                                                                        pyrazolylmethyl                                                      l                                                                          5412                                                                             1-indolylmethyl                                                                        1-       3-methylpentyl                                                                         3-methylpentyl                                              imidazolylmethy                                                               l                                                                 5413                                                                             2-pyridylmethyl                                                                        1-indolylmethyl                                                                        3-pentyl 3-pentyl                                        5414                                                                             3-pyridylmethyl                                                                        2-pyridylmethyl                                                                        4-methylpentyl                                                                         4-methylpentyl                                  5415                                                                             4-pyridylmethyl                                                                        3-pyridylmethyl                                                                        3,3-dimethallyl                                                                        3,3-dimethallyl                                 5416                                                                             cyclohexylmethy                                                                        4-pyridylmethyl                                                                        3,3-     3,3-                                               l                 dimethylbutyl                                                                          dimethylbutyl                                   5417                                                                             2-       cyclohexylmethy                                                                        allyl    allyl                                              thiophenylmethy                                                                        l                                                                    l                                                                          5418                                                                             (3,4-    2-       cyclobutylmethy                                                                        cyclobutylmethy                                    methylenedioxyp                                                                        thiophenylmethy                                                                        l        l                                                  henyl)methyl                                                                           l                                                                 5419                                                                             2-thienylmethyl                                                                        (3,4-    cyclopropylmeth                                                                        cyclopropylmeth                                             methylenedioxyp                                                                        yl       yl                                              5420                                                                             4-       henyl)methyl                                                         biphenylmethyl                                                                         2-thienylmethyl                                                                        isobutyl isobutyl                                        5421                                                                             2-       4-                                                                   thiomethylethyl                                                                        biphenylmethyl                                                                         n-butyl  n-butyl                                         5422                                                                             p-       2-                                                                   hydroxyphenylme                                                                        thiomethylethyl                                                                        n-pentyl n-pentyl                                           thyl                                                                       5423                                                                             p-       p-       propyl   propyl                                             nitrophenylmeth                                                                        hydroxyphenylme                                                      yl       thyl                                                              5424                                                                             benzyl   p-       2-methallyl                                                                            2-methallyl                                                 nitrophenylmeth                                                               yl                                                                5425                                                                             1-pyrolylmethyl                                                                        benzyl   4-methylpentyl                                                                         4-methylpentyl                                  5426                                                                             1-       1-pyrolylmethyl                                                                        3-methallyl                                                                            3-methallyl                                        pyrazolylmethyl                                                            5427                                                                             1-       1-       3-methylbutyl                                                                          3-methylbutyl                                      imidazolylmethy                                                                        pyrazolylmethyl                                                      l                                                                          5428                                                                             1-indolylmethyl                                                                        1-       3-methylpentyl                                                                         3-methylpentyl                                              imidazolylmethy                                                               l                                                                 5429                                                                             2-pyridylmethyl                                                                        1-indolylmethyl                                                                        3-pentyl 3-pentyl                                        5430                                                                             3-pyridylmethyl                                                                        2-pyridylmethyl                                                                        4-methylpentyl                                                                         4-methylpentyl                                  5431                                                                             4-pyridylmethyl                                                                        3-pyridylmethyl                                                                        3,3-dimethallyl                                                                        3,3-dimethallyl                                 5432                                                                             cyclohexylmethy                                                                        4-pyridylmethyl                                                                        3,3-     3,3-                                               l                 dimethylbutyl                                                                          dimethylbutyl                                   5433                                                                             2-       cyclohexylmethy                                                                        allyl    allyl                                              thiophenylmethy                                                                        l                                                                    l                                                                          5434                                                                             (3,4-    2-       cyclobutylmethy                                                                        cyclobutylmethy                                    methylenedioxyp                                                                        thiophenylmethy                                                                        l        l                                                  henyl)methyl                                                                           l                                                                 5435                                                                             2-thienylmethyl                                                                        (3,4-    cyclopropylmeth                                                                        cyclopropylmeth                                             methylenedioxyp                                                                        yl       yl                                                          henyl)methyl                                                      5436                                                                             4-       2-thienylmethyl                                                                        isobutyl isobutyl                                           biphenylmethyl                                                             5437                                                                             2-       4-       n-butyl  n-butyl                                            thiomethylethyl                                                                        biphenylmethyl                                                    5438                                                                             p-       2-       n-pentyl n-pentyl                                           hydroxyphenylme                                                                        thiomethylethyl                                                      thyl                                                                       5439                                                                             p-       p-       propyl   propyl                                             nitrophenylmeth                                                                        hydroxyphenylme                                                      yl       thyl                                                              5440                                                                             benzyl   p-       2-methallyl                                                                            propyl                                                      nitrophenylmeth                                                               yl                                                                5441                                                                             1-pyrolylmethyl                                                                        benzyl   4-methylpentyl                                                                         2-methallyl                                     5442                                                                             1-       1-pyrolylmethyl                                                                        3-methallyl                                                                            4-methylpentyl                                     pyrazolylmethyl                                                            5443                                                                             1-       1-       3-methylbutyl                                                                          3-methallyl                                        imidazolylmethy                                                                        pyrazolylmethyl                                                      l                                                                          5444                                                                             1-indolylmethyl                                                                        1-       3-methylpentyl                                                                         3-methylbutyl                                               imidazolylmethy                                                               l                                                                 5445                                                                             2-pyridylmethyl                                                                        1-indolylmethyl                                                                        3-pentyl 3-methylpentyl                                  5446                                                                             3-pyridylmethyl                                                                        2-pyridylmethyl                                                                        4-methylpentyl                                                                         3-pentyl                                        5447                                                                             4-pyridylmethyl                                                                        3-pyridylmethyl                                                                        3,3-dimethallyl                                                                        4-methylpentyl                                  5448                                                                             cyclohexylmethy                                                                        4-pyridylmethyl                                                                        3,3-     3,3-dimethallyl                                    l                 dimethylbutyl                                            5449                                                                             2-       cyclohexylmethy                                                                        allyl    3,3-                                               thiophenylmethy                                                                        l                 dimethylbutyl                                      l                                                                          5450                                                                             (3,4-    2-       cyclobutylmethy                                                                        allyl                                              methylenedioxyp                                                                        thiophenylmethy                                                                        l                                                           henyl)methyl                                                                           l                                                                 5451                                                                             2-thienylmethyl                                                                        (3,4-    cyclopropylmeth                                                                        cyclobutylmethy                                             methylenedioxyp                                                                        yl       l                                                           henyl)methyl                                                      5452                                                                             4-       2-thienylmethyl                                                                        isobutyl cyclopropylmeth                                    biphenylmethyl             yl                                              5453                                                                             2-       4-       n-butyl  isobutyl                                           thiomethylethyl                                                                        biphenylmethyl                                                    5454                                                                             p-       2-       n-pentyl n-butyl                                            hydroxyphenylme                                                                        thiomethylethyl                                                      thyl                                                                       5455                                                                             p-       p-       propyl   n-pentyl                                           nitrophenylmeth                                                                        hydroxyphenylme                                                      yl       thyl                                                              __________________________________________________________________________

                  TABLE 14                                                        ______________________________________                                         ##STR101##                                                                   Ex.                                                                           No.  R4           R7           R22                                            ______________________________________                                        5456 benzyl       benzyl       2-methallyl                                    5457 1-pyrolylmethyl                                                                            1-pyrolylmethyl                                                                            4-methylpentyl                                 5458 1-pyrazolylmethyl                                                                          1-pyrazolylmethyl                                                                          3-methallyl                                    5459 1-           1-           3-methylbutyl                                       imidazolylmethyl                                                                           imidazolylmethyl                                            5460 1-indolylmethyl                                                                            1-indolylmethyl                                                                            3-methylpentyl                                 5461 2-pyridylmethyl                                                                            2-pyridylmethyl                                                                            3-pentyl                                       5462 3-pyridylmethyl                                                                            3-pyridylmethyl                                                                            4-methylpentyl                                 5463 4-pyridylmethyl                                                                            4-pyridylmethyl                                                                            3,3-dimethallyl                                5464 cyclohexylmethyl                                                                           cyclohexylmethyl                                                                           3,3-dimethylbutyl                              5465 2-           2-           allyl                                               thiophenylmethyl                                                                           thiophenylmethyl                                            5466 (3,4-        (3,4-        cyclobutylmethyl                                    methylenedioxyphe                                                                          methylenedioxyphe                                                nyl)methyl   nyl)methyl                                                  5467 2-thienylmethyl                                                                            2-thienylmethyl                                                                            cyclopropylmethyl                              5468 4-biphenylmethyl                                                                           4-biphenylmethyl                                                                           isobutyl                                       5469 2-thiomethylethyl                                                                          2-thiomethylethyl                                                                          n-butyl                                        5470 p-           p-           n-pentyl                                            hydroxyphenylmeth                                                                          hydroxyphenylmeth                                                yl           yl                                                          5471 p-           p-           propyl                                              nitrophenylmethyl                                                                          nitrophenylmethyl                                           5472 benzyl       benzyl       2-methallyl                                    5473 1-pyrolylmethyl                                                                            1-pyrolylmethyl                                                                            4-methylpentyl                                 5474 1-pyrazolylmethyl                                                                          1-pyrazolylmethyl                                                                          3-methallyl                                    5475 1-           1-           3-methylbutyl                                       imidazolylmethyl                                                                           imidazolylmethyl                                            5476 1-indolylmethyl                                                                            1-indolylmethyl                                                                            3-methylpentyl                                 5477 2-pyridylmethyl                                                                            2-pyridylmethyl                                                                            3-pentyl                                       5478 3-pyridylmethyl                                                                            3-pyridylmethyl                                                                            4-methylpentyl                                 5479 4-pyridylmethyl                                                                            4-pyridylmethyl                                                                            3,3-dimethallyl                                5480 cyclohexylmethyl                                                                           cyclohexylmethyl                                                                           3,3-dimethylbutyl                              5481 2-           2-           allyl                                               thiophenylmethyl                                                                           thiophenylmethyl                                            5482 (3,4-        (3,4-        cyclobutylmethyl                                    methylenedioxyphe                                                                          methylenedioxyphe                                                nyl)methyl   nyl)methyl                                                  5483 2-thienylmethyl                                                                            2-thienylmethyl                                                                            cyclopropylmethyl                              5484 4-biphenylmethyl                                                                           4-biphenylmethyl                                                                           isobutyl                                       5485 2-thiomethylethyl                                                                          2-thiomethylethyl                                                                          n-butyl                                        5486 p-           p-           n-pentyl                                            hydroxyphenylmeth                                                                          hydroxyphenylmeth                                                yl           yl                                                          5487 p-           p-           propyl                                              nitrophenylmethyl                                                                          nitrophenylmethyl                                           5488 benzyl       p-           2-methallyl                                                      nitrophenylmethyl                                           5489 1-pyrolylmethyl                                                                            benzyl       4-methylpentyl                                 5490 1-pyrazolylmethyl                                                                          1-pyrolylmethyl                                                                            3-methallyl                                    5491 1-           1-pyrazolylmethyl                                                                          3-methylbutyl                                       imidazolylmethyl                                                         5492 1-indolylmethyl                                                                            1-           3-methylpentyl                                                   imidazolylmethyl                                            5493 2-pyridylmethyl                                                                            1-indolylmethyl                                                                            3-pentyl                                       5494 3-pyridylmethyl                                                                            2-pyridylmethyl                                                                            4-methylpentyl                                 5495 4-pyridylmethyl                                                                            3-pyridylmethyl                                                                            3,3-dimethallyl                                5496 cyclohexylmethyl                                                                           4-pyridylmethyl                                                                            3,3-dimethylbutyl                              5497 2-           cyclohexylmethyl                                                                           allyl                                               thiophenylmethyl                                                         5498 (3,4-        2-           cyclobutylmethyl                                    methylenedioxyphe                                                                          thiophenylmethyl                                                 nyl)methyl                                                               5499 2-thienylmethyl                                                                            (3,4-        cyclopropylmethyl                                                methylenedioxyphe                                                             nyl)methyl                                                  5500 4-biphenylmethyl                                                                           2-thienylmethyl                                                                            isobutyl                                       5501 2-thiomethylethyl                                                                          4-biphenylmethyl                                                                           n-butyl                                        5502 p-           2-thiomethylethyl                                                                          n-pentyl                                            hydroxyphenylmeth                                                             yl                                                                       5503 p-           p-           propyl                                              nitrophenylmethyl                                                                          hydroxyphenylmeth                                                             yl                                                          5504 benzyl       p-           2-methallyl                                                      nitrophenylmethyl                                           5505 1-pyrolylmethyl                                                                            benzyl       4-methylpentyl                                 5506 1-pyrazolylmethyl                                                                          1-pyrolylmethyl                                                                            3-methallyl                                    5507 1-           1-pyrazolylmethyl                                                                          3-methylbutyl                                       imidazolylmethyl                                                         5508 1-indolylmethyl                                                                            1-           3-methylpentyl                                                   imidazolylmethyl                                            5509 2-pyridylmethyl                                                                            1-indolylmethyl                                                                            3-pentyl                                       5510 3-pyridylmethyl                                                                            2-pyridylmethyl                                                                            4-methylpentyl                                 5511 4-pyridylmethyl                                                                            3-pyridylmethyl                                                                            3,3-dimethallyl                                5512 cyclohexylmethyl                                                                           4-pyridylmethyl                                                                            3,3-dimethylbutyl                              5513 2-           cyclohexylmethyl                                                                           allyl                                               thiophenylmethyl                                                         5514 (3,4-        2-           cyclobutylmethyl                                    methylenedioxyphe                                                                          thiophenylmethyl                                                 nyl)methyl                                                               5515 2-thienylmethyl                                                                            (3,4-        cyclopropylmethyl                                                methylenedioxyphe                                                             nyl)methyl                                                  5516 4-biphenylmethyl                                                                           2-thienylmethyl                                                                            isobutyl                                       5517 2-thiomethylethyl                                                                          4-biphenylmethyl                                                                           n-butyl                                        5518 p-           2-thiomethylethyl                                                                          n-pentyl                                            hydroxyphenylmeth                                                             yl                                                                       5519 p-           p-           propyl                                              nitrophenylmethyl                                                                          hydroxyphenylmeth                                                             yl                                                          5520 benzyl       p-           2-methallyl                                                      nitrophenylmethyl                                           5521 1-pyrolylmethyl                                                                            benzyl       4-methylpentyl                                 5522 1-pyrazolylmethyl                                                                          1-pyrolylmethyl                                                                            3-methallyl                                    5523 1-           1-pyrazolylmethyl                                                                          3-methylbutyl                                       imidazolylmethyl                                                         5524 1-indolylmethyl                                                                            1-           3-methylpentyl                                                   imidazolylmethyl                                            5525 2-pyridylmethyl                                                                            1-indolylmethyl                                                                            3-pentyl                                       5526 3-pyridylmethyl                                                                            2-pyridylmethyl                                                                            4-methylpentyl                                 5527 4-pyridylmethyl                                                                            3-pyridylmethyl                                                                            3,3-dimethallyl                                5528 cyclohexylmethyl                                                                           4-pyridylmethyl                                                                            3,3-dimethylbutyl                              5529 2-           cyclohexylmethyl                                                                           allyl                                               thiophenylmethyl                                                         5530 (3,4-        2-           cyclobutylmethyl                                    methylenedioxyphe                                                                          thiophenylmethyl                                                 nyl)methyl                                                               5531 2-thienylmethyl                                                                            (3,4-        cyclopropylmethyl                                                methylenedioxyphe                                                             nyl)methyl                                                  5532 4-biphenylmethyl                                                                           2-thienylmethyl                                                                            isobutyl                                       5533 2-thiomethylethyl                                                                          4-biphenylmethyl                                                                           n-butyl                                        5534 p-           2-thiomethylethyl                                                                          n-pentyl                                            hydroxyphenylmeth                                                             yl                                                                       5535 p-           p-           propyl                                              nitrophenylmethyl                                                                          hydroxyphenylmeth                                                             yl                                                          ______________________________________                                    

                  TABLE 15                                                        ______________________________________                                         ##STR102##                                                                   Ex.                                                                           No.  R4           R7           R22                                            ______________________________________                                        5536 benzyl       benzyl       2-methallyl                                    5537 1-pyrolylmethyl                                                                            1-pyrolylmethyl                                                                            4-methylpentyl                                 5538 1-pyrazolylmethyl                                                                          1-pyrazolylmethyl                                                                          3-methallyl                                    5539 1-           1-           3-methylbutyl                                       imidazolylmethyl                                                                           imidazolylmethyl                                            5540 1-indolylmethyl                                                                            1-indolylmethyl                                                                            3-methylpentyl                                 5541 2-pyridylmethyl                                                                            2-pyridylmethyl                                                                            3-pentyl                                       5542 3-pyridylmethyl                                                                            3-pyridylmethyl                                                                            4-methylpentyl                                 5543 4-pyridylmethyl                                                                            4-pyridylmethyl                                                                            3,3-dimethallyl                                5544 cyclohexylmethyl                                                                           cyclohexylmethyl                                                                           3,3-dimethylbutyl                              5545 2-           2-           allyl                                               thiophenylmethyl                                                                           thiophenylmethyl                                            5546 (3,4-        (3,4-        cyclobutylmethyl                                    methylenedioxyphe                                                                          methylenedioxyphe                                                nyl)methyl   nyl)methyl                                                  5547 2-thienylmethyl                                                                            2-thienylmethyl                                                                            cyclopropylmethyl                              5548 4-biphenylmethyl                                                                           4-biphenylmethyl                                                                           isobutyl                                       5549 2-thiomethylethyl                                                                          2-thiomethylethyl                                                                          n-butyl                                        5550 p-           p-           n-pentyl                                            hydroxyphenylmeth                                                                          hydroxyphenylmeth                                                yl           yl                                                          5551 p-           p-           propyl                                              nitrophenylmethyl                                                                          nitrophenylmethyl                                           5552 benzyl       benzyl       2-methallyl                                    5553 1-pyrolylmethyl                                                                            1-pyrolylmethyl                                                                            4-methylpentyl                                 5554 1-pyrazolylmethyl                                                                          1-pyrazolylmethyl                                                                          3-methallyl                                    5555 1-           1-           3-methylbutyl                                       imidazolylmethyl                                                                           imidazolylmethyl                                            5556 1-indolylmethyl                                                                            1-indolylmethyl                                                                            3-methylpentyl                                 5557 2-pyridylmethyl                                                                            2-pyridylmethyl                                                                            3-pentyl                                       5558 3-pyridylmethyl                                                                            3-pyridylmethyl                                                                            4-methylpentyl                                 5559 4-pyridylmethyl                                                                            4-pyridylmethyl                                                                            3,3-dimethallyl                                5560 cyclohexylmethyl                                                                           cyclohexylmethyl                                                                           3,3-dimethylbutyl                              5561 2-           2-           allyl                                               thiophenylmethyl                                                                           thiophenylmethyl                                            5562 (3,4-        (3,4-        cyclobutylmethyl                                    methylenedioxyphe                                                                          methylenedioxyphe                                                nyl)methyl   nyl)methyl                                                  5563 2-thienylmethyl                                                                            2-thienylmethyl                                                                            cyclopropylmethyl                              5564 4-biphenylmethyl                                                                           4-biphenylmethyl                                                                           isobutyl                                       5565 2-thiomethylethyl                                                                          2-thiomethylethyl                                                                          n-butyl                                        5566 p-           p-           n-pentyl                                            hydroxyphenylmeth                                                                          hydroxyphenylmeth                                                yl           yl                                                          5567 p-           p-           propyl                                              nitrophenylmethyl                                                                          nitrophenylmethyl                                           5568 benzyl       p-           2-methallyl                                                      nitrophenylmethyl                                           5569 1-pyrolylmethyl                                                                            benzyl       4-methylpentyl                                 5570 1-pyrazolylmethyl                                                                          1-pyrolylmethyl                                                                            3-methallyl                                    5571 1-           1-pyrazolylmethyl                                                                          3-methylbutyl                                       imidazolylmethyl                                                         5572 1-indolylmethyl                                                                            1-           3-methylpentyl                                                   imidazolylmethyl                                            5573 2-pyridylmethyl                                                                            1-indolylmethyl                                                                            3-pentyl                                       5574 3-pyridylmethyl                                                                            2-pyridylmethyl                                                                            4-methylpentyl                                 5575 4-pyridylmethyl                                                                            3-pyridylmethyl                                                                            3,3-dimethallyl                                5576 cyclohexylmethyl                                                                           4-pyridylmethyl                                                                            3,3-dimethylbutyl                              5577 2-           cyclohexylmethyl                                                                           allyl                                               thiophenylmethyl                                                         5578 (3,4-        2-           cyclobutylmethyl                                    methylenedioxyphe                                                                          thiophenylmethyl                                                 nyl)methyl                                                               5579 2-thienylmethyl                                                                            (3,4-        cyclopropylmethyl                                                methylenedioxyphe                                                             nyl)methyl                                                  5580 4-biphenylmethyl                                                                           2-thienylmethyl                                                                            isobutyl                                       5581 2-thiomethylethyl                                                                          4-biphenylmethyl                                                                           n-butyl                                        5582 p-           2-thiomethylethyl                                                                          n-pentyl                                            hydroxyphenylmeth                                                             yl                                                                       5583 p-           p-           propyl                                              nitrophenylmethyl                                                                          hydroxyphenylmeth                                                             yl                                                          5584 benzyl       p-           2-methallyl                                                      nitrophenylmethyl                                           5585 1-pyrolylmethyl                                                                            benzyl       4-methylpentyl                                 5586 1-pyrazolylmethyl                                                                          1-pyrolylmethyl                                                                            3-methallyl                                    5587 1-           1-pyrazolylmethyl                                                                          3-methylbutyl                                       imidazolylmethyl                                                         5588 1-indolylmethyl                                                                            1-           3-methylpentyl                                                   imidazolylmethyl                                            5589 2-pyridylmethyl                                                                            1-indolylmethyl                                                                            3-pentyl                                       5590 3-pyridylmethyl                                                                            2-pyridylmethyl                                                                            4-methylpentyl                                 5591 4-pyridylmethyl                                                                            3-pyridylmethyl                                                                            3,3-dimethallyl                                5592 cyclohexylmethyl                                                                           4-pyridylmethyl                                                                            3,3-dimethylbutyl                              5593 2-           cyclohexylmethyl                                                                           allyl                                               thiophenylmethyl                                                         5594 (3,4-        2-           cyclobutylmethyl                                    methylenedioxyphe                                                                          thiophenylmethyl                                                 nyl)methyl                                                               5595 2-thienylmethyl                                                                            (3,4-        cyclopropylmethyl                                                methylenedioxyphe                                                             nyl)methyl                                                  5596 4-biphenylmethyl                                                                           2-thienylmethyl                                                                            isobutyl                                       5597 2-thiomethylethyl                                                                          4-biphenylmethyl                                                                           n-butyl                                        5598 p-           2-thiomethylethyl                                                                          n-pentyl                                            hydroxyphenylmeth                                                             yl                                                                       5599 p-           p-           propyl                                              nitrophenylmethyl                                                                          hydroxyphenylmeth                                                             yl                                                          5600 benzyl       p-           2-methallyl                                                      nitrophenylmethyl                                           5601 1-pyrolylmethyl                                                                            benzyl       4-methylpentyl                                 5602 1-pyrazolylmethyl                                                                          1-pyrolylmethyl                                                                            3-methallyl                                    5603 1-           1-pyrazolylmethyl                                                                          3-methylbutyl                                       imidazolylmethyl                                                         5604 1-indolylmethyl                                                                            1-           3-methylpentyl                                                   imidazolylmethyl                                            5605 2-pyridylmethyl                                                                            1-indolylmethyl                                                                            3-pentyl                                       5606 3-pyridylmethyl                                                                            2-pyridylmethyl                                                                            4-methylpentyl                                 5607 4-pyridylmethyl                                                                            3-pyridylmethyl                                                                            3,3-dimethallyl                                5608 cyclohexylmethyl                                                                           4-pyridylmethyl                                                                            3,3-dimethylbutyl                              5609 2-           cyclohexylmethyl                                                                           allyl                                               thiophenylmethyl                                                         5610 (3,4-        2-           cyclobutylmethyl                                    methylenedioxyphe                                                                          thiophenylmethyl                                                 nyl)methyl                                                               5611 2-thienylmethyl                                                                            (3,4-        cyclopropylmethyl                                                methylenedioxyphe                                                             nyl)methyl                                                  5612 4-biphenylmethyl                                                                           2-thienylmethyl                                                                            isobutyl                                       5613 2-thiomethylethyl                                                                          4-biphenylmethyl                                                                           n-butyl                                        5614 p-           2-thiomethylethyl                                                                          n-pentyl                                            hydroxyphenylmeth                                                             yl                                                                       5615 p-           p-           propyl                                              nitrophenylmethyl                                                                          hydroxyphenylmeth                                                             yl                                                          ______________________________________                                    

                  TABLE 16                                                        ______________________________________                                        Example                                                                       Number                                                                        ______________________________________                                        5616                                                                                    ##STR103##                                                          5617                                                                                    ##STR104##                                                          5618                                                                                    ##STR105##                                                          5619                                                                                    ##STR106##                                                          ______________________________________                                    

                  TABLE 17                                                        ______________________________________                                         ##STR107##                                                                   Ex.  R.sup.22       R.sup.23     R.sup.4 = R.sup.7                            ______________________________________                                        5620 (m-hydroxymethyl)                                                                            (m-tetrazolyl)benzyl                                                                       benzyl                                            benzyl                                                                   5621 (p-hydroxymethyl)benzyl                                                                      (m-tetrazolyl)benzyl                                                                       benzyl                                       5622 (m-hydroxy)benzyl                                                                            (m-tetrazolyl)benzyl                                                                       benzyl                                       5623 (p-hydroxy)benzyl                                                                            (m-tetrazolyl)benzyl                                                                       benzyl                                       5624 (m-carboxamido)benzyl                                                                        (m-tetrazolyl)benzyl                                                                       benzyl                                       5625 (m-(N-methyl   (m-tetrazolyl)benzyl                                                                       benzyl                                            carboxamido))benzyl                                                      5626 (m-hydroxymethyl)                                                                            (m-imidazolyl)                                                                             benzyl                                            benzyl         benzyl                                                    5627 (p-hydroxymethyl)benzyl                                                                      (m-imidazolyl)                                                                             benzyl                                                           benzyl                                                    5628 (m-hydroxy)benzyl                                                                            (m-imidazolyl)                                                                             benzyl                                                           benzyl                                                    5629 (p-hydroxy)benzyl                                                                            (m-imidazolyl)                                                                             benzyl                                                           benzyl                                                    5630 (m-carboxamido)benzyl                                                                        (m-imidazolyl)                                                                             benzyl                                                           benzyl                                                    5631 (m-(N-methyl   (m-imidazolyl)                                                                             benzyl                                            carboxamido))benzyl                                                                          benzyl                                                    5632 (m-hydroxymethyl)                                                                            (m-tetrazolyl)benzyl                                                                       (p-fluoro)benzyl                                  benzyl                                                                   5633 (p-hydroxymethyl)benzyl                                                                      (m-tetrazolyl)benzyl                                                                       (p-fluoro)benzyl                             5634 (m-hydroxy)benzyl                                                                            (m-tetrazolyl)benzyl                                                                       (p-fluoro)benzyl                             5635 (p-hydroxy)benzyl                                                                            (m-tetrazolyl)benzyl                                                                       (p-fluoro)benzyl                             5636 (m-carboxamido)benzyl                                                                        (m-tetrazolyl)benzyl                                                                       (p-fluoro)benzyl                             5637 (m-(N-methyl   (m-tetrazolyl)benzyl                                                                       (p-fluoro)benzyl                                  carboxamido))benzyl                                                      5638 (m-hydroxymethyl)                                                                            (m-imidazolyl)                                                                             (p-fluoro)benzyl                                  benzyl         benzyl                                                    5639 (p-hydroxymethyl)benzyl                                                                      (m-imidazolyl)                                                                             (p-fluoro)benzyl                                                 benzyl                                                    5640 (m-hydroxy)benzyl                                                                            (m-imidazolyl)                                                                             (p-fluoro)benzyl                                                 benzyl                                                    5641 (p-hydroxy)benzyl                                                                            (m-imidazolyl)                                                                             (p-fluoro)benzyl                                                 benzyl                                                    5642 (m-carboxamido)benzyl                                                                        (m-imidazolyl)                                                                             (p-fluoro)benzyl                                                 benzyl                                                    5643 (m-(N-methyl   (m-imidazolyl)                                                                             (p-fluoro)benzyl                                  carboxamido))benzyl                                                                          benzyl                                                    5644 (m-carboxy)benzyl                                                                            (m-hydroxy)benzyl                                                                          benzyl                                       5645 (m-carboxy)benzyl                                                                            (p-hydroxy)benzyl                                                                          benzyl                                       5646 (m-carboxy)benzyl                                                                            (m-hydroxymethyl)                                                                          benzyl                                                           benzyl                                                    5647 (m-carboxy)benzyl                                                                            (p-hydroxymethyl)                                                                          benzyl                                                           benzyl                                                    5648 (m-carboxy)benzyl                                                                            (m-carboxamido)                                                                            benzyl                                                           benzyl                                                    5649 (m-carboxy)benzyl                                                                            (m-(N-methyl benzyl                                                           carboxamido))                                                                 benzyl                                                    5650 (m-carboxy)benzyl                                                                            (m-acetyl)benzyl                                                                           benzyl                                       5651 (m-carboxy)benzyl                                                                            (m-glycolyl)benzyl                                                                         benzyl                                       5652 (m-carboxy)benzyl                                                                            (m-sulfonamido)                                                                            benzyl                                                           benzyl                                                    5653 (m-carboxy)benzyl                                                                            (m-(N-methyl-                                                                              benzyl                                                           amino)benzyl                                              5654 (m-carboxamido)benzyl                                                                        (m-hydroxy)benzyl                                                                          benzyl                                       5655 (m-carboxamido)benzyl                                                                        (p-hydroxy)benzyl                                                                          benzyl                                       5656 (m-carboxamido)benzyl                                                                        (m-hydroxymethyl)                                                                          benzyl                                                           benzyl                                                    5657 (m-carboxamido)benzyl                                                                        (p-hydroxymethyl)                                                                          benzyl                                                           benzyl                                                    5658 (m-carboxamido)benzyl                                                                        (m-carboxamido)                                                                            benzyl                                                           benzyl                                                    5659 (m-carboxamido)benzyl                                                                        (m-(N-methyl benzyl                                                           carboxamido))                                                                 benzyl                                                    5660 (m-carboxamido)benzyl                                                                        (m-acetyl)benzyl                                                                           benzyl                                       5661 (m-carboxamido)benzyl                                                                        (m-glycolyl)benzyl                                                                         benzyl                                       5662 (m-carboxamido)benzyl                                                                        (m-sulfonamido)                                                                            benzyl                                                           benzyl                                                    5663 (m-carboxamido)benzyl                                                                        (m-(N-methyl-                                                                              benzyl                                                           amino)benzyl                                              5664 (m-(N-methyl   (m-hydroxy)benzyl                                                                          benzyl                                            carboxamido))benzyl                                                      5665 (m-(N-methyl   (p-hydroxy)benzyl                                                                          benzyl                                            carboxamido))benzyl                                                      5666 (m-(N-methyl   (m-hydroxymethyl)                                                                          benzyl                                            carboxamido))benzyl                                                                          benzyl                                                    5667 (m-(N-methyl   (p-hydroxymethyl)                                                                          benzyl                                            carboxamido))benzyl                                                                          benzyl                                                    5668 (m-(N-methyl   (m-carboxamido)                                                                            benzyl                                            carboxamido))benzyl                                                                          benzyl                                                    5669 (m-(N-methyl   (m-(N-methyl benzyl                                            carboxamido))benzyl                                                                          carboxamido))                                                                 benzyl                                                    5670 (m-(N-methyl   (m-acetyl)benzyl                                                                           benzyl                                            carboxamido))benzyl                                                      5671 (m-(N-methyl   (m-glycolyl)benzyl                                                                         benzyl                                            carboxamido))benzyl                                                      5672 (m-(N-methyl   (m-sulfonamido)                                                                            benzyl                                            carboxamido))benzyl                                                                          benzyl                                                    5673 (m-(N-methyl   (m-(N-methyl-                                                                              benzyl                                            carboxamido))benzyl                                                                          amino)benzyl                                              5674 (m-sulfonamido)benzyl                                                                        (m-hydroxy)benzyl                                                                          benzyl                                       5675 (m-sulfonamido)benzyl                                                                        (p-hydroxy)benzyl                                                                          benzyl                                       5676 (m-sulfonamido)benzyl                                                                        (m-hydroxymethyl)                                                                          benzyl                                                           benzyl                                                    5677 (m-sulfonamido)benzyl                                                                        (p-hydroxymethyl)                                                                          benzyl                                                           benzyl                                                    5678 (m-sulfonamido)benzyl                                                                        (m-carboxamido)                                                                            benzyl                                                           benzyl                                                    5679 (m-sulfonamido)benzyl                                                                        (m-(N-methyl benzyl                                                           carboxamido))                                                                 benzyl                                                    5680 (m-sulfonamido)benzyl                                                                        (m-acetyl)benzyl                                                                           benzyl                                       5681 (m-sulfonamido)benzyl                                                                        (m-glycolyl)benzyl                                                                         benzyl                                       5682 (m-sulfonamido)benzyl                                                                        (m-sulfonamido)                                                                            benzyl                                                           benzyl                                                    5683 (m-sulfonamido)benzyl                                                                        (m-(N-methyl-                                                                              benzyl                                                           amino)benzyl                                              5684 m-(N-ethylcarboxamido)                                                                       (m-hydroxy)benzyl                                                                          benzyl                                            benzyl                                                                   5685 m-(N-ethylcarboxamido)                                                                       (p-hydroxy)benzyl                                                                          benzyl                                            benzyl                                                                   5686 m-(N-ethylcarboxamido)                                                                       (m-hydroxymethyl)                                                                          benzyl                                            benzyl         benzyl                                                    5687 m-(N-ethylcarboxamido)                                                                       (p-hydroxymethyl)                                                                          benzyl                                            benzyl         benzyl                                                    5688 m-(N-ethylcarboxamido)                                                                       (m-carboxamido)                                                                            benzyl                                            benzyl         benzyl                                                    5689 m-(N-ethylcarboxamido)                                                                       (m-(N-methyl benzyl                                            benzyl         carboxamido))                                                                 benzyl                                                    5690 m-(N-ethylcarboxamido)                                                                       (m-acetyl)benzyl                                                                           benzyl                                            benzyl                                                                   5691 m-(N-ethylcarboxamido)                                                                       (m-glycolyl)benzyl                                                                         benzyl                                            benzyl                                                                   5692 m-(N-ethylcarboxamido)                                                                       (m-sulfonamido)                                                                            benzyl                                            benzyl         benzyl                                                    5693 m-(N-ethylcarboxamido)                                                                       (m-(N-methyl-                                                                              benzyl                                            benzyl         amino)benzyl                                              5694 3-pyridylmethyl                                                                              (m-hydroxy)benzyl                                                                          benzyl                                       5695 3-pyridylmethyl                                                                              (p-hydroxy)benzyl                                                                          benzyl                                       5696 3-pyridylmethyl                                                                              (m-hydroxymethyl)                                                                          benzyl                                                           benzyl                                                    5697 3-pyridylmethyl                                                                              (p-hydroxymethyl)                                                                          benzyl                                                           benzyl                                                    5698 3-pyridylmethyl                                                                              (m-carboxamido)                                                                            benzyl                                                           benzyl                                                    5699 3-pyridylmethyl                                                                              (m-(N-methyl benzyl                                                           carboxamido))                                                                 benzyl                                                    5700 3-pyridylmethyl                                                                              (m-acetyl)benzyl                                                                           benzyl                                       5701 3-pyridylmethyl                                                                              (m-glycolyl)benzyl                                                                         benzyl                                       5702 3-pyridylmethyl                                                                              (m-sulfonamido)                                                                            benzyl                                                           benzyl                                                    5703 3-pyridylmethyl                                                                              (m-(N-methyl-                                                                              benzyl                                                           amino)benzyl                                              5704 (m-carboxy)benzyl                                                                            (m-hydroxy)benzyl                                                                          (p-fluoro)benzyl                             5705 (m-carboxy)benzyl                                                                            (p-hydroxy)benzyl                                                                          (p-fluoro)benzyl                             5706 (m-carboxy)benzyl                                                                            (m-hydroxymethyl)                                                                          (p-fluoro)benzyl                                                 benzyl                                                    5707 (m-carboxy)benzyl                                                                            (p-hydroxymethyl)                                                                          (p-fluoro)benzyl                                                 benzyl                                                    5708 (m-carboxy)benzyl                                                                            (m-carboxamido)                                                                            (p-fluoro)benzyl                                                 benzyl                                                    5709 (m-carboxy)benzyl                                                                            (m-(N-methyl (p-fluoro)benzyl                                                 carboxamido))                                                                 benzyl                                                    5710 (m-carboxy)benzyl                                                                            (m-acetyl)benzyl                                                                           (p-fluoro)benzyl                             5711 (m-carboxy)benzyl                                                                            (m-glycolyl)benzyl                                                                         (p-fluoro)benzyl                             5712 (m-carboxy)benzyl                                                                            (m-sulfonamido)                                                                            (p-fluoro)benzyl                                                 benzyl                                                    5713 (m-carboxy)benzyl                                                                            (m-(N-methyl-                                                                              (p-fluoro)benzyl                                                 amino)benzyl                                              5714 (m-carboxamido)benzyl                                                                        (m-hydroxy)benzyl                                                                          (p-fluoro)benzyl                             5715 (m-carboxamido)benzyl                                                                        (p-hydroxy)benzyl                                                                          (p-fluoro)benzyl                             5716 (m-carboxamido)benzyl                                                                        (m-hydroxymethyl)                                                                          (p-fluoro)benzyl                                                 benzyl                                                    5717 (m-carboxamido)benzyl                                                                        (p-hydroxymethyl)                                                                          (p-fluoro)benzyl                                                 benzyl                                                    5718 (m-carboxamido)benzyl                                                                        (m-carboxamido)                                                                            (p-fluoro)benzyl                                                 benzyl                                                    5719 (m-carboxamido)benzyl                                                                        (m-(N-methyl (p-fluoro)benzyl                                                 carboxamido))                                                                 benzyl                                                    5720 (m-carboxamido)benzyl                                                                        (m-acetyl)benzyl                                                                           (p-fluoro)benzyl                             5721 (m-carboxamido)benzyl                                                                        (m-glycolyl)benzyl                                                                         (p-fluoro)benzyl                             5722 (m-carboxamido)benzyl                                                                        (m-sulfonamido)                                                                            (p-fluoro)benzyl                                                 benzyl                                                    5723 (m-carboxamido)benzyl                                                                        (m-(N-methyl-                                                                              (p-fluoro)benzyl                                                 amino)benzyl                                              5724 (m-(N-methyl   (m-hydroxy)benzyl                                                                          (p-fluoro)benzyl                                  carboxamido))benzyl                                                      5725 (m-(N-methyl   (p-hydroxy)benzyl                                                                          (p-fluoro)benzyl                                  carboxamido))benzyl                                                      5726 (m-(N-methyl   (m-hydroxymethyl)                                                                          (p-fluoro)benzyl                                  carboxamido))benzyl                                                                          benzyl                                                    5727 (m-(N-methyl   (p-hydroxymethyl)                                                                          (p-fluoro)benzyl                                  carboxamido))benzyl                                                                          benzyl                                                    5728 (m-(N-methyl   (m-carboxamido)                                                                            (p-fluoro)benzyl                                  carboxamido))benzyl                                                                          benzyl                                                    5729 (m-(N-methyl   (m-(N-methyl (p-fluoro)benzyl                                  carboxamido))benzyl                                                                          carboxamido))                                                                 benzyl                                                    5730 (m-(N-methyl   (m-acetyl)benzyl                                                                           (p-fluoro)benzyl                                  carboxamido))benzyl                                                      5731 (m-(N-methyl   (m-glycolyl)benzyl                                                                         (p-fluoro)benzyl                                  carboxamido))benzyl                                                      5732 (m-(N-methyl   (m-sulfonamido)                                                                            (p-fluoro)benzyl                                  carboxamido))benzyl                                                                          benzyl                                                    5733 (m-(N-methyl   (m-(N-methyl-                                                                              (p-fluoro)benzyl                                  carboxamido))benzyl                                                                          amino)benzyl                                              5734 (m-sulfonamido)benzyl                                                                        (m-hydroxy)benzyl                                                                          (p-fluoro)benzyl                             5735 (m-sulfonamido)benzyl                                                                        (p-hydroxy)benzyl                                                                          (p-fluoro)benzyl                             5736 (m-sulfonamido)benzyl                                                                        (m-hydroxymethyl)                                                                          (p-fluoro)benzyl                                                 benzyl                                                    5737 (m-sulfonamido)benzyl                                                                        (p-hydroxymethyl)                                                                          (p-fluoro)benzyl                                                 benzyl                                                    5738 (m-sulfonamido)benzyl                                                                        (m-carboxamido)                                                                            (p-fluoro)benzyl                                                 benzyl                                                    5739 (m-sulfonamido)benzyl                                                                        (m-(N-methyl (p-fluoro)benzyl                                                 carboxainido))                                                                benzyl                                                    5740 (m-sulfonamido)benzyl                                                                        (m-acetyl)benzyl                                                                           (p-fluoro)benzyl                             5741 (m-sulfonamido)benzyl                                                                        (m-glycolyl)benzyl                                                                         (p-fluoro)benzyl                             5742 (m-sulfonamido)benzyl                                                                        (m-sulfonamido)                                                                            (p-fluoro)benzyl                                                 benzyl                                                    5743 (m-sulfonamido)benzyl                                                                        (m-(N-methyl-                                                                              (p-fluoro)benzyl                                                 amino)benzyl                                              5744 m-(N-ethylcarboxamido)                                                                       (m-hydroxy)benzyl                                                                          (p-fluoro)benzyl                                  benzyl                                                                   5745 m-(N-ethylcarboxamido)                                                                       (p-hydroxy)benzyl                                                                          (p-fluoro)benzyl                                  benzyl                                                                   5746 m-(N-ethylcarboxamido)                                                                       (m-hydroxymethyl)                                                                          (p-fluoro)benzyl                                  benzyl         benzyl                                                    5747 m-(N-ethylcarboxamido)                                                                       (p-hydroxymethyl)                                                                          (p-fluoro)benzyl                                  benzyl         benzyl                                                    5748 m-(N-ethylcarboxamido)                                                                       (m-carboxamido)                                                                            (p-fluoro)benzyl                                  benzyl         benzyl                                                    5749 m-(N-ethylcarboxamido)                                                                       (m-(N-methyl (p-fluoro)benzyl                                  benzyl         carboxamido))                                                                 benzyl                                                    5750 m-(N-ethylcarboxamido)                                                                       (m-acetyl)benzyl                                                                           (p-fluoro)benzyl                                  benzyl                                                                   5751 m-(N-ethylcarboxamido)                                                                       (m-glycolyl)benzyl                                                                         (p-fluoro)benzyl                                  benzyl                                                                   5752 m-(N-ethylcarboxamido)                                                                       (m-sulfonamido)                                                                            (p-fluoro)benzyl                                  benzyl         benzyl                                                    5753 m-(N-ethylcarboxamido)                                                                       (m-(N-methyl-                                                                              (p-fluoro)benzyl                                  benzyl         amino)benzyl                                              5754 3-pyridylmethyl                                                                              (m-hydroxy)benzyl                                                                          (p-fluoro)benzyl                             5755 3-pyridylmethyl                                                                              (p-hydroxy)benzyl                                                                          (p-fluoro)benzyl                             5756 3-pyridylmethyl                                                                              (m-hydroxymethyl)                                                                          (p-fluoro)benzyl                                                 benzyl                                                    5757 3-pyridylmethyl                                                                              (p-hydroxymethyl)                                                                          (p-fluoro)benzyl                                                 benzyl                                                    5758 3-pyridylmethyl                                                                              (m-carboxamido)                                                                            (p-fluoro)benzyl                                                 benzyl                                                    5759 3-pyridylmethyl                                                                              (m-(N-methyl (p-fluoro)benzyl                                                 carboxamido))                                                                 benzyl                                                    5760 3-pyridylmethyl                                                                              (m-acetyl)benzyl                                                                           (p-fluoro)benzyl                             5761 3-pyridylmethyl                                                                              (m-glycolyl)benzyl                                                                         (p-fluoro)benzyl                             5762 3-pyridylmethyl                                                                              (m-sulfonamido)                                                                            (p-fluoro)benzyl                                                 benzyl                                                    5763 3-pyridylmethyl                                                                              (m-(N-methyl-                                                                              (p-fluoro)benzyl                                                 amino)benzyl                                              ______________________________________                                    

                  TABLE 18                                                        ______________________________________                                         ##STR108##                                                                   Example                                                                       Number   R.sup.4 = R.sup.7  R.sup.22 = R.sup.23                               ______________________________________                                        5764     benzyl             allyl                                             5765     1-pyrolylmethyl    allyl                                             5766     1-pyrazolylmethyl  allyl                                             5767     1-imidazolylmethyl allyl                                             5768     1-indolylmethyl    allyl                                             5769     1-triazolylmethyl  allyl                                             5770     1-tetrazolylmethyl allyl                                             5771     2-pyridylmethyl    allyl                                             5772     3-pyridylmethyl    allyl                                             5773     4-pyridylmethyl    allyl                                             5774     cyclohexylmethyl   allyl                                             5775     2-naphthylmethyl   allyl                                             5776     3-naphthylmethyl   allyl                                             5777     2-thiophenylmethyl allyl                                             5778     4-(1-methyl)piperidinyl-                                                                         allyl                                                      methyl                                                               5779     "(3,4-             allyl                                                      methylenedioxyphenyl)methyl"                                         5780     2-thienylmethyl    allyl                                             5781     4-biphenylmethyl   allyl                                             5782     pyrimidinylmethyl  allyl                                             5783     2-benzothiazolylmethyl                                                                           allyl                                             5784     2-benzothiophenylmethyl                                                                          allyl                                             5785     2-thiomethylethyl  allyl                                             5786     2-thiomethylmethyl allyl                                             5787     2-methylpropyl     allyl                                             5788     2-methylbutyl      allyl                                             5789     3-methylbutyl      allyl                                             5790     cyclopropylmethyl  allyl                                             5791     cyclobutylmethyl   allyl                                             5792     cyclopentylmethyl  allyl                                             5793     p-hydroxyphenylmethyl                                                                            allyl                                             5794     p-nitrophenylmethyl                                                                              allyl                                             5795     p-aminophenylmethyl                                                                              allyl                                             5796     "4-(N,N-           allyl                                                      dimethylamino)phenylmethyl"                                          5797     benzyl             propyl                                            5798     1-pyrolylmethyl    propyl                                            5799     1-pyrazolylmethyl  propyl                                            5800     1-imidazolylmethyl propyl                                            5801     1-indolylmethyl    propyl                                            5802     1-triazolylmethyl  propyl                                            5803     1-tetrazolylmethyl propyl                                            5804     2-pyridylmethyl    propyl                                            5805     3-pyridylmethyl    propyl                                            5806     4-pyridylmethyl    propyl                                            5807     cyclohexylmethyl   propyl                                            5808     2-naphthylmethyl   propyl                                            5809     3-naphthylmethyl   propyl                                            5810     2-thiophenylmethyl propyl                                            5811     4-(1-methyl)piperidinyl-                                                                         propyl                                                     methyl                                                               5812     "(3,4-             propyl                                                     methylenedioxyphenyl)methyl"                                         5813     2-thienylmethyl    propyl                                            5814     4-biphenylmethyl   propyl                                            5815     pyrimidinylmethyl  propyl                                            5816     2-benzothiazolylmethyl                                                                           propyl                                            5817     2-benzothiophenylmethyl                                                                          propyl                                            5818     2-thiomethylethyl  propyl                                            5819     2-thiomethylmethyl propyl                                            5820     2-methylpropyl     propyl                                            5821     2-methylbutyl      propyl                                            5822     3-methylbutyl      propyl                                            5823     cyclopropylmethyl  propyl                                            5824     cyclobutylmethyl   propyl                                            5825     cyclopentylmethyl  propyl                                            5826     p-hydroxyphenylmethyl                                                                            propyl                                            5827     p-nitrophenylmethyl                                                                              propyl                                            5828     p-aminophenylmethyl                                                                              propyl                                            5829     "4-(N,N-           propyl                                                     dimethylamino)phenylmethyl"                                          5830     benzyl             n-butyl                                           5831     1-pyrolylmethyl    n-butyl                                           5832     1-pyrazolylmethyl  n-butyl                                           5833     1-imidazolylmethyl n-butyl                                           5834     1-indolylmethyl    n-butyl                                           5835     1-triazolylmethyl  n-butyl                                           5836     1-tetrazolylmethyl n-butyl                                           5837     2-pyridylmethyl    n-butyl                                           5838     3-pyridylmethyl    n-butyl                                           5839     4-pyridylmethyl    n-butyl                                           5840     cyclohexylmethyl   n-butyl                                           5841     2-naphthylmethyl   n-butyl                                           5842     3-naphthylmethyl   n-butyl                                           5843     2-thiophenylmethyl n-butyl                                           5844     4-(1-methyl)piperidinyl-                                                                         n-butyl                                                    methyl                                                               5845     "(3,4-             n-butyl                                                    methylenedioxyphenyl)methyl"                                         5846     2-thienylmethyl    n-butyl                                           5847     4-biphenylmethyl   n-butyl                                           5848     pyrimidinylmethyl  n-butyl                                           5849     2-benzothiazolylmethyl                                                                           n-butyl                                           5850     2-benzothiophenylmethyl                                                                          n-butyl                                           5851     2-thiomethylethyl  n-butyl                                           5852     2-thiomethylmethyl n-butyl                                           5853     2-methylpropyl     n-butyl                                           5854     2-methylbutyl      n-butyl                                           5855     3-methylbutyl      n-butyl                                           5856     cyclopropylmethyl  n-butyl                                           5857     cyclobutylmethyl   n-butyl                                           5858     cyclopentylmethyl  n-butyl                                           5859     p-hydroxyphenylmethyl                                                                            n-butyl                                           5860     p-nitrophenylmethyl                                                                              n-butyl                                           5861     p-aminophenylmethyl                                                                              n-butyl                                           5862     "4-(N,N-           n-butyl                                                    dimethylamino)phenylmethyl"                                          5929     benzyl             "3,3-dimethallyl"                                 5930     1-pyrolylmethyl    "3,3-dimethallyl"                                 5931     1-pyrazolylmethyl  "3,3-dimethallyl"                                 5932     1-imidazolylmethyl "3,3-dimethallyl"                                 5933     1-indolylmethyl    "3,3-dimethallyl"                                 5934     1-triazolylmethyl  "3,3-dimethallyl"                                 5935     1-tetrazolylmethyl "3,3-dimethallyl"                                 5936     2-pyridylmethyl    "3,3-dimethallyl"                                 5937     3-pyridylmethyl    "3,3-dimethallyl"                                 5938     4-pyridylmethyl    "3,3-dimethallyl"                                 5939     cyclohexylmethyl   "3,3-dimethallyl"                                 5940     2-naphthylmethyl   "3,3-dimethallyl"                                 5941     3-naphthylmethyl   "3,3-dimethallyl"                                 5942     2-thiophenylmethyl "3,3-dimethallyl"                                 5943     4-(1-methyl)piperidinyl-                                                                         "3,3-dimethallyl"                                          methyl                                                               5944     "(3,4-             "3,3-dimethallyl"                                          methylenedioxyphenyl)methyl"                                         5945     2-thienylmethyl    "3,3-dimethallyl"                                 5946     4-biphenylmethyl   "3,3-dimethallyl"                                 5947     pyrimidinylmethyl  "3,3-dimethallyl"                                 5948     2-benzothiazolylmethyl                                                                           "3,3-dimethallyl"                                 5949     2-benzothiophenylmethyl                                                                          "3,3-dimethallyl"                                 5950     2-thiomethylethyl  "3,3-dimethallyl"                                 5951     2-thiomethylmethyl "3,3-dimethallyl"                                 5952     2-methylpropyl     "3,3-dimethallyl"                                 ______________________________________                                    

                                      TABLE 19                                    __________________________________________________________________________     ##STR109##                                                                   Example                                                                       Number                                                                              R.sup.4     R.sup.7    R.sup.22 = R.sup.23                              __________________________________________________________________________    6984  benzyl      "4-(N,N-   allyl                                                              dimethylamino)phenyl-                                                         methyl"                                                     6985  1-pyrolylmethyl                                                                           benzyl     allyl                                            6986  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          allyl                                            6987  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        allyl                                            6988  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       allyl                                            6989  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          allyl                                            6990  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        allyl                                            6991  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       allyl                                            6992  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          allyl                                            6993  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          allyl                                            6994  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          allyl                                            6995  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         allyl                                            6996  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         allyl                                            6997  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         allyl                                            6998  4-(1-methyl)piper-                                                                        2-thiophenylmethyl                                                                       allyl                                                  idinylmethyl                                                            6999  "(3,4-methylenedioxy-                                                                     4-(1-methyl)piperi-                                                                      allyl                                                  phenyl)methyl"                                                                            dinyl-methyl                                                7000  2-thienylmethyl                                                                           "(3,4-methylenedioxy                                                                     allyl                                                              phenyl)methyl"                                              7001  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          allyl                                            7002  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         allyl                                            7003  2-benzothiazolyl-                                                                         pyrimidinylmethyl                                                                        allyl                                                  methyl                                                                  7004  2-benzothiophenyl-                                                                        2-benzothiazolyl-                                                                        allyl                                                  methyl      methyl                                                      7005  2-thiomethylethyl                                                                         2-benzothiophenyl-                                                                       allyl                                                              methyl                                                      7006  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        allyl                                            7007  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       allyl                                            7008  2-methylbutyl                                                                             2-methylpropyl                                                                           allyl                                            7009  3-methylbutyl                                                                             2-methylbutyl                                                                            allyl                                            7010  cyclopropylmethyl                                                                         3-methylbutyl                                                                            allyl                                            7011  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        allyl                                            7012  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         allyl                                            7013  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        allyl                                            7014  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   allyl                                            7015  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      allyl                                            7016  "4-(N,N-dimethyl-                                                                         p-aminophenyl-methyl                                                                     allyl                                                  amino)phenylmethyl"                                                     7017  benzyl      "4-(N,N-dimethyl-                                                                        propyl                                                             amino)-phenyl-methyl"                                       7018  1-pyrolylmethyl                                                                           benzyl     propyl                                           7019  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          propyl                                           7020  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        propyl                                           7021  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       propyl                                           7022  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          propyl                                           7023  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        propyl                                           7024  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       propyl                                           7025  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          propyl                                           7026  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          propyl                                           7027  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          propyl                                           7028  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         propyl                                           7029  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         propyl                                           7030  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         propyl                                           7031  4-(1-methyl)-                                                                 piperidinyl-methyl                                                                        2-thiophenylmethyl                                                                       propyl                                           7032  "(3,4-methylene-                                                                          4-(1-methyl)-                                                     dioxyphenyl)methyl"                                                                       piperidinyl-methyl                                                                       propyl                                           7033  2-thienylmethyl                                                                           "(3,4-methylene-                                                                         propyl                                                             dioxyphenyl)methyl"                                         7034  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          propyl                                           7035  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         propyl                                           7036  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        propyl                                           7037  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   propyl                                           7038  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  propyl                                           7039  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        propyl                                           7040  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       propyl                                           7041  2-methylbutyl                                                                             2-methylpropyl                                                                           propyl                                           7042  3-methylbutyl                                                                             2-methylbutyl                                                                            propyl                                           7043  cyclopropylmethyl                                                                         3-methylbutyl                                                                            propyl                                           7044  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        propyl                                           7045  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         propyl                                           7046  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        propyl                                           7047  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   propyl                                           7048  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      propyl                                           7049  "4-(N,N-dimethyl-                                                                         p-aminophenyl-methyl                                                                     propyl                                                 amino)phenylmethyl"                                                     7050  benzyl      "4-(N,N-dimethyl-                                                                        n-butyl                                                            amino)phenylmethyl"                                         7051  1-pyrolylmethyl                                                                           benzyl     n-butyl                                          7052  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          n-butyl                                          7053  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        n-butyl                                          7054  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       n-butyl                                          7055  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          n-butyl                                          7056  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        n-butyl                                          7057  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       n-butyl                                          7058  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          n-butyl                                          7059  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          n-butyl                                          7060  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          n-butyl                                          7061  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         n-butyl                                          7062  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         n-butyl                                          7063  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         n-butyl                                          7064  4-(1-methyl)-                                                                             2-thiophenylmethyl                                                                       n-butyl                                                piperidinyl-methyl                                                      7065  "(3,4-      4-(1-methyl)-                                                                            n-butyl                                                methylenedioxyphenyl)                                                                     piperidinyl-methyl                                                methyl"                                                                 7066  2-thienylmethyl                                                                           "(3,4-methylene-                                                                         n-butyl                                                            dioxyphenyl)methyl"                                         7067  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          n-butyl                                          7068  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         n-butyl                                          7069  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        n-butyl                                          7070  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   n-butyl                                          7071  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  n-butyl                                          7072  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        n-butyl                                          7073  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       n-butyl                                          7074  2-methylbutyl                                                                             2-methylpropyl                                                                           n-butyl                                          7075  3-methylbutyl                                                                             2-methylbutyl                                                                            n-butyl                                          7076  cyclopropylmethyl                                                                         3-methylbutyl                                                                            n-butyl                                          7077  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        n-butyl                                          7078  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         n-butyl                                          7079  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        n-butyl                                          7080  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   n-butyl                                          7081  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      n-butyl                                          7082  "4-(N,N-dimethyl-                                                                         p-aminophenyl-methyl                                                                     n-butyl                                                amino)phenyl-methyl"                                                    7149  benzyl      "4-(N,N-dimethyl-                                                                        "3,3-dimethallyl"                                                  amino)phenylmethyl"                                         7150  1-pyrolylmethyl                                                                           benzyl     "3,3-dimethallyl"                                7151  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          "3,3-dimethallyl"                                7152  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        "3,3-dimethallyl"                                7153  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       "3,3-dimethallyl"                                7154  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          "3,3-dimethallyl"                                7155  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        "3,3-dimethallyl"                                7156  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       "3,3-dimethallyl"                                7157  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          "3,3-dimethallyl"                                7158  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          "3,3-dimethallyl"                                7159  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          "3,3-dimethallyl"                                7160  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         "3,3-dimethallyl"                                7161  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         "3,3-dimethallyl"                                7162  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         "3,3-dimethallyl"                                7163  4-(1-       2-thiophenylmethyl                                                                       "3,3-dimethallyl"                                      methyl)piperidinyl-                                                           methyl                                                                  7164  "(3,4-      4-(1-      "3,3-dimethallyl"                                      methylenedioxyphenyl)                                                                     methyl)piperidinyl-                                               methyl"     methyl                                                      7165  2-thienylmethyl                                                                           "(3,4-methylene-                                                                         "3,3-dimethallyl"                                                  dioxyphenyl)methyl"                                         7166  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          "3,3-dimethallyl"                                7167  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         "3,3-dimethallyl"                                7168  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        "3,3-dimethallyl"                                7169  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   "3,3-dimethallyl"                                7170  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  "3,3-dimethallyl"                                7171  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        "3,3-dimethallyl"                                7172  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       "3,3-dimethallyl"                                7173  2-methylbutyl                                                                             2-methylpropyl                                                                           "3,3-dimethallyl"                                7174  3-methylbutyl                                                                             2-methylbutyl                                                                            "3,3-dimethallyl"                                7175  cyclopropylmethyl                                                                         3-methylbutyl                                                                            "3,3-dimethallyl"                                7176  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        "3,3-dimethallyl"                                7177  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         "3,3-dimethallyl"                                7178  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        "3,3-dimethallyl"                                7179  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   "3,3-dimethallyl"                                7180  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      "3,3-dimethallyl"                                7181  "4-(N,N-    p-aminophenyl-methyl                                                                     "3,3-dimethallyl"                                      dimethylamino)phenyl-                                                         methyl"                                                                 7182  benzyl      "4-(N,N-   3-methallyl                                                        dimethylamino)-phenyl-                                                        methyl"                                                     7183  1-pyrolylmethyl                                                                           benzyl     3-methallyl                                      7184  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          3-methallyl                                      7185  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        3-methallyl                                      7186  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       3-methallyl                                      7187  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          3-methallyl                                      7188  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        3-methallyl                                      7189  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       3-methallyl                                      7190  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          3-methallyl                                      7191  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          3-methallyl                                      7192  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          3-methallyl                                      7193  2-naphthylmethyl                                                                          cyclchexylmethyl                                                                         3-methallyl                                      7194  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         3-methallyl                                      7195  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         3-methallyl                                      7196  4-(1-methyl)-                                                                             2-thiophenylmethyl                                                                       3-methallyl                                            piperidinyl-methyl                                                      7197  "(3,4-      4-(1-      3-methallyl                                            methylenedioxyphenyl)                                                                     methyl)piperidinyl-                                               methyl"     methyl                                                      7918  2-thienylmethyl                                                                           "(3,4-methylene-                                                                         3-methallyl                                                        dioxyphenyl)methyl"                                         7199  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          3-methallyl                                      7200  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         3-methallyl                                      7201  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        3-methallyl                                      7202  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   3-methallyl                                      7203  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  3-methallyl                                      7204  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        3-methallyl                                      7205  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       3-methallyl                                      7206  2-methylbutyl                                                                             2-methylpropyl                                                                           3-methallyl                                      7207  3-methylbutyl                                                                             2-methylbutyl                                                                            3-methallyl                                      7208  cyclopropylmethyl                                                                         3-methylbutyl                                                                            3-methallyl                                      7209  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        3-methallyl                                      7210  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         3-methallyl                                      7211  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        3-methallyl                                      7212  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   3-methallyl                                      7213  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      3-methallyl                                      7214  "4-(N,N-dimethyl-                                                                         p-aminophenyl-methyl                                                                     3-methallyl                                            amino)-phenyl-methyl"                                                   7215  benzyl      "4-(N,N-dimethyl-                                                                        2-methallyl                                                        amino)phenylmethyl"                                         7216  1-pyrolylmethyl                                                                           benzyl     2-methallyl                                      7217  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          2-methallyl                                      7218  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        2-methallyl                                      7219  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       2-methallyl                                      7220  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          2-methallyl                                      7221  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        2-methallyl                                      7222  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       2-methallyl                                      7223  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          2-methallyl                                      7224  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          2-methallyl                                      7225  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          2-methallyl                                      7226  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         2-methallyl                                      7227  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         2-methallyl                                      7228  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         2-methallyl                                      7229  4-(1-       2-thiophenylmethyl                                                                       2-methallyl                                            methyl)piperidinyl-                                                           methyl                                                                  7230  "(3,4-methylene-                                                                          4-(1-methyl)-                                                                            2-methallyl                                            dioxyphenyl)methyl"                                                                       piperidinyl-methyl                                          7231  2-thienylmethyl                                                                           "(3,4-methylene-                                                                         2-methallyl                                                        dioxyphenyl)methyl"                                         7232  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          2-methallyl                                      7233  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         2-methallyl                                      7234  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        2-methallyl                                      7235  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   2-methallyl                                      7236  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  2-methallyl                                      7237  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        2-methallyl                                      7238  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       2-methallyl                                      7239  2-methylbutyl                                                                             2-methylpropyl                                                                           2-methallyl                                      7240  3-methylbutyl                                                                             2-methylbutyl                                                                            2-methallyl                                      7241  cyclopropylmethyl                                                                         3-methylbutyl                                                                            2-methallyl                                      7242  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        2-methallyl                                      7243  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         2-methallyl                                      7244  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        2-methallyl                                      7245  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   2-methallyl                                      7246  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      2-methallyl                                      7247  "4-(N,N-dimethyl-                                                                         p-aminophenyl-methyl                                                                     2-methallyl                                            amino)-phenylmethyl"                                                    7314  benzyl      "4-(N,N-   cyclopropylmethyl                                                  dimethylamino)phenyl-                                                         methyl"                                                     7315  1-pyrolylmethyl                                                                           benzyl     cyclopropylmethyl                                7316  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          cyclopropylmethyl                                7317  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        cyclopropylmethyl                                7318  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       cyclopropylmethyl                                7319  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          cyclopropylmethyl                                7320  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        cyclopropylmethyl                                7321  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       cyclopropylmethyl                                7322  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          cyclopropylmethyl                                7323  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          cyclopropylmethyl                                7324  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          cyclopropylmethyl                                7325  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         cyclopropylmethyl                                7326  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         cyclopropylmethyl                                7327  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         cyclopropylmethyl                                7328  4-(1-       2-thiophenylmethyl                                                                       cyclopropylmethyl                                      methyl)piperidinyl-                                                           methyl                                                                  7329  "(3,4-      4-(1-      cyclopropylmethyl                                      methylenedioxyphenyl)                                                                     methyl)piperidinyl-                                               methyl"     methyl                                                      7330  2-thienylmethyl                                                                           "(3,4-     cyclopropylmethyl                                                  methylenedioxyphenyl)                                                         methyl"                                                     7331  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          cyclopropylmethyl                                7332  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         cyclopropylmethyl                                7333  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        cyclopropylmethyl                                7334  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   cyclopropylmethyl                                7335  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  cyclopropylmethyl                                7336  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        cyclopropylmethyl                                7337  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       cyclopropylmethyl                                7338  2-methylbutyl                                                                             2-methylpropyl                                                                           cyclopropylmethyl                                7339  3-methylbutyl                                                                             2-methylbutyl                                                                            cyclopropylmethyl                                7340  cyclopropylmethyl                                                                         3-methylbutyl                                                                            cyclopropylmethyl                                7341  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        cyclopropylmethyl                                7342  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         cyclopropylmethyl                                7343  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        cyclopropylmethyl                                7344  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   cyclopropylmethyl                                7345  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      cyclopropylmethyl                                7346  "4-(N,N-    p-aminophenyl-methyl                                                                     cyclopropylmethyl                                      dimethylamino)phenyl-                                                         methyl"                                                                 7347  benzyl      "4-(N,N-   n-pentyl                                                           dimethylamino)phenyl-                                                         methyl"                                                     7348  1-pyrolylmethyl                                                                           benzyl     n-pentyl                                         7349  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          n-pentyl                                         7350  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        n-pentyl                                         7351  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       n-pentyl                                         7352  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          n-pentyl                                         7353  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        n-pentyl                                         7354  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       n-pentyl                                         7355  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          n-pentyl                                         7356  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          n-pentyl                                         7357  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          n-pentyl                                         7358  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         n-pentyl                                         7359  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         n-pentyl                                         7360  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         n-pentyl                                         7361  4-(1-       2-thiophenylmethyl                                                                       n-pentyl                                               methyl)piperidinyl-                                                           methyl                                                                  7362  "(3,4-      4-(1-      n-pentyl                                               methylenedioxyphenyl)                                                                     methyl)piperidinyl-                                               methyl"     methyl                                                      7363  2-thienylmethyl                                                                           "(3,4-     n-pentyl                                                           methylenedioxyphenyl)                                                         methyl"                                                     7364  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          n-pentyl                                         7365  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         n-pentyl                                         7366  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        n-pentyl                                         7367  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   n-pentyl                                         7368  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  n-pentyl                                         7369  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        n-pentyl                                         7370  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       n-pentyl                                         7371  2-methylbutyl                                                                             2-methylpropyl                                                                           n-pentyl                                         7372  3-methylbutyl                                                                             2-methylbutyl                                                                            n-pentyl                                         7373  cyclopropylmethyl                                                                         3-methylbutyl                                                                            n-pentyl                                         7374  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        n-pentyl                                         7375  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         n-pentyl                                         7376  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        n-pentyl                                         7377  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   n-pentyl                                         7378  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      n-pentyl                                         7379  "4-(N,N-    p-aminophenyl-methyl                                                                     n-pentyl                                               dimethylamino)phenyl-                                                         methyl"                                                                 7512  benzyl      "4-(N,N-   propargyl                                                          dimethylamino)phenyl-                                                         methyl"                                                     7513  1-pyrolylmethyl                                                                           benzyl     propargyl                                        7514  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          propargyl                                        7515  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        propargyl                                        7516  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       propargyl                                        7517  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          propargyl                                        7518  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        propargyl                                        7519  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       propargyl                                        7520  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          propargyl                                        7521  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          propargyl                                        7522  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          propargyl                                        7523  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         propargyl                                        7524  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         propargyl                                        7525  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         propargyl                                        7526  4-(1-       2-thiophenylmethyl                                                                       propargyl                                              methyl)piperidinyl-                                                           methyl                                                                  7527  "(3,4-      4-(1-      propargyl                                              methylenedioxyphenyl)                                                                     methyl)piperidinyl-                                               methyl"     methyl                                                      7528  2-thienylmethyl                                                                           "(3,4-     propargyl                                                          methylenedioxyphenyl)                                                         methyl"                                                     7529  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          propargyl                                        7530  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         propargyl                                        7531  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        propargyl                                        7532  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   propargyl                                        7533  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  propargyl                                        7534  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        propargyl                                        7535  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       propargyl                                        7536  2-methylbutyl                                                                             2-methylpropyl                                                                           propargyl                                        7537  3-methylbutyl                                                                             2-methylbutyl                                                                            propargyl                                        7538  cyclopropylmethyl                                                                         3-methylbutyl                                                                            propargyl                                        7539  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        propargyl                                        7540  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         propargyl                                        7541  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        propargyl                                        7542  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   propargyl                                        7543  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      propargyl                                        7544  "4-(N,N-    p-aminophenyl-methyl                                                                     propargyl                                              dimethylamino)phenyl-                                                         methyl"                                                                 7578  benzyl      "4-(N,N-   cyclobutylmethyl                                                   dimethylamino)phenyl-                                                         methyl"                                                     7579  1-pyrolylmethyl                                                                           benzyl     cyclobutylmethyl                                 7580  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          cyclobutylmethyl                                 7581  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        cyclobutylmethyl                                 7582  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       cyclobutylmethyl                                 7583  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          cyclobutylmethyl                                 7584  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        cyclobutylmethyl                                 7585  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       cyclobutylmethyl                                 7586  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          cyclobutylmethyl                                 7587  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          cyclobutylmethyl                                 7588  cyclohexylmethyl                                                                          4-pyridyimethyl                                                                          cyclobutylmethyl                                 7589  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         cyclobutylmethyl                                 7590  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         cyclobutylmethyl                                 7591  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         cyclobutylmethyl                                 7592  4-(1-       2-thiophenylmethyl                                                                       cyclobutylmethyl                                       methyl)piperidinyl-                                                           methyl                                                                  7593  "(3,4-      4-(1-      cyclobutylmethyl                                       methylenedioxyphenyl)                                                                     methyl)piperidinyl-                                               methyl"     methyl                                                      7594  2-thienylmethyl                                                                           "(3,4-     cyclobutylmethyl                                                   methylenedioxyphenyl)                                                         methyl"                                                     7595  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          cyclobutylmethyl                                 7596  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         cyclobutylmethyl                                 7597  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        cyclobutylmethyl                                 7598  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   cyclobutylmethyl                                 7599  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  cyclobutylmethyl                                 7600  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        cyclobutylmethyl                                 7601  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       cyclobutylmethyl                                 7602  2-methylbutyl                                                                             2-methylpropyl                                                                           cyclobutylmethyl                                 7603  3-methylbutyl                                                                             2-methylbutyl                                                                            cyclobutylmethyl                                 7604  cyclopropylmethyl                                                                         3-methylbutyl                                                                            cyclobutylmethyl                                 7605  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        cyclobutylmethyl                                 7606  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         cyclobutylmethyl                                 7607  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        cyclobutylmethyl                                 7608  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   cyclobutylmethyl                                 7609  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      cyclobutylmethyl                                 7610  "4-(N,N-    p-aminophenyl-methyl                                                                     cyclobutylmethyl                                       dimethylamino)phenyl-                                                         methyl"                                                                 7644  benzyl      "4-(N,N-   cyclopentylmethyl                                                  dimethylamino)phenyl-                                                         methyl"                                                     7645  1-pyrolylmethyl                                                                           benzyl     cyclopentylmethyl                                7646  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          cyclopentylmethyl                                7647  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        cyclopentylmethyl                                7648  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       cyclopentylmethyl                                7649  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          cyclopentylmethyl                                7650  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        cyclopentylmethyl                                7651  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       cyclopentylmethyl                                7652  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          cyclopentylmethyl                                7653  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          cyclopentylmethyl                                7654  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          cyclopentylmethyl                                7655  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         cyclopentylmethyl                                7656  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         cyclopentylmethyl                                7657  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         cyclopentylmethyl                                7658  4-(1-       2-thiophenylmethyl                                                                       cyclopentylmethyl                                      methyl)piperidinyl-                                                           methyl                                                                  7659  "(3,4-      4-(1-      cyclopentylmethyl                                      methylenedioxyphenyl)                                                                     methyl)piperidinyl                                                methyl"     methyl                                                      7660  2-thienylmethyl                                                                           "(3,4-     cyclopentylmethyl                                                  methylenedioxyphenyl)                                                         methyl"                                                     7661  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          cyclopentylmethyl                                7662  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         cyclopentylmethyl                                7663  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        cyclopentylmethyl                                7664  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   cyclopentylmethyl                                7665  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  cyclopentylmethyl                                7666  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        cyclopentylmethyl                                7667  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       cyclopentylmethyl                                7668  2-methylbutyl                                                                             2-methylpropyl                                                                           cyclopentylmethyl                                7669  3-methylbutyl                                                                             2-methylbutyl                                                                            cyclopentylmethyl                                7670  cyclopropylmethyl                                                                         3-methylbutyl                                                                            cyclopentylmethyl                                7671  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        cyclopentylmethyl                                7672  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         cyclopentylmethyl                                7673  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        cyclopentylmethyl                                7674  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   cyclopentylmethyl                                7675  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      cyclopentylmethyl                                7676  "4-(N,N-    p-aminophenyl-methyl                                                                     cyclopentylmethyl                                      dimethylamino)phenyl-                                                         methyl"                                                                 7677  benzyl      "4-(N,N-   1-hexyl                                                            dimethylamino)phenyl-                                                         methyl"                                                     7678  1-pyrolylmethyl                                                                           benzyl     1-hexyl                                          7679  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          1-hexyl                                          7680  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        1-hexyl                                          7681  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       1-hexyl                                          7682  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          1-hexyl                                          7683  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        1-hexyl                                          7684  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       1-hexyl                                          7685  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          1-hexyl                                          7686  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          1-hexyl                                          7687  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          1-hexyl                                          7688  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         1-hexyl                                          7689  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         1-hexyl                                          7690  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         1-hexyl                                          7691  4-(1-       2-thiophenylmethyl                                                                       1-hexyl                                                methyl)piperidinyl-                                                           methyl                                                                  7692  "(3,4-      4-(1-      1-hexyl                                                methylenedioxyphenyl)                                                                     methyl)piperidinyl-                                               methyl"     methyl                                                      7693  2-thienylmethyl                                                                           "(3,4-     1-hexyl                                                            methylenedioxyphenyl)                                                         methyl"                                                     7694  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          1-hexyl                                          7695  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         1-hexyl                                          7696  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        1-hexyl                                          7697  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   1-hexyl                                          7698  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  1-hexyl                                          7699  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        1-hexyl                                          7700  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       1-hexyl                                          7701  2-methylbutyl                                                                             2-methylpropyl                                                                           1-hexyl                                          7702  3-methylbutyl                                                                             2-methylbutyl                                                                            1-hexyl                                          7703  cyclopropylmethyl                                                                         3-methylbutyl                                                                            1-hexyl                                          7704  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        1-hexyl                                          7705  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         1-hexyl                                          7706  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        1-hexyl                                          7707  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   1-hexyl                                          7708  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      1-hexyl                                          7709  "4-(N,N-    p-aminophenyl-methyl                                                                     1-hexyl                                                dimethylamino)phenyl-                                                         methyl"                                                                 7842  benzyl      "4-(N,N-   2-phenylethyl                                                      dimethylamino)phenyl-                                                         methyl"                                                     7843  1-pyrolylmethyl                                                                           benzyl     2-phenylethyl                                    7844  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          2-phenylethyl                                    7845  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        2-phenylethyl                                    7846  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       2-phenylethyl                                    7847  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          2-phenylethyl                                    7848  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        2-phenylethyl                                    7849  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       2-phenylethyl                                    7850  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          2-phenylethyl                                    7851  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          2-phenylethyl                                    7852  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          2-phenylethyl                                    7853  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         2-phenylethyl                                    7854  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         2-phenylethyl                                    7855  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         2-phenylethyl                                    7856  4-(1-       2-thiophenylmethyl                                                                       2-phenylethyl                                          methyl)piperidinyl-                                                           methyl                                                                  7857  "(3,4-      4-(1-      2-phenylethyl                                          methylenedioxyphenyl)                                                                     methyl)piperidinyl-                                               methyl"     methyl                                                      7858  2-thienylmethyl                                                                           "(3,4-     2-phenylethyl                                                      methylenedioxyphenyl)                                                         methyl"                                                     7859  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          2-phenylethyl                                    7860  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         2-phenylethyl                                    7861  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        2-phenylethyl                                    7862  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   2-phenylethyl                                    7863  2-thiomethylethyl                                                                         2-benzothlophenylmethyl                                                                  2-phenylethyl                                    7864  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        2-phenylethyl                                    7865  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       2-phenylethyl                                    7866  2-methylbutyl                                                                             2-methylpropyl                                                                           2-phenylethyl                                    7867  3-methylbutyl                                                                             2-methylbutyl                                                                            2-phenylethyl                                    7868  cyclopropylmethyl                                                                         3-methylbutyl                                                                            2-phenylethyl                                    7869  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        2-phenylethyl                                    7870  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         2-phenylethyl                                    7871  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        2-phenylethyl                                    7872  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   2-phenylethyl                                    7873  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      2-phenylethyl                                    7874  "4-(N,N-    p-aminophenyl-methyl                                                                     2-phenylethyl                                          dimethylamino)phenyl-                                                         methyl"                                                                 7875  benzyl      "4-(N,N-   3-phenylpropyl                                                     dimethylamino)phenyl-                                                         methyl"                                                     7876  1-pyrolylmethyl                                                                           benzyl     3-phenylpropyl                                   7877  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          3-phenylpropyl                                   7878  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        3-phenylpropyl                                   7879  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       3-phenylpropyl                                   7880  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          3-phenylpropyl                                   7881  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        3-phenylpropyl                                   7882  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       3-phenylpropyl                                   7883  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          3-phenylpropyl                                   7884  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          3-phenylpropyl                                   7885  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          3-phenylpropyl                                   7886  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         3-phenylpropyl                                   7887  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         3-phenylpropyl                                   7888  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         3-phenylpropyl                                   7889  4-(1-       2-thiophenylmethyl                                                                       3-phenylpropyl                                         methyl)piperidinyl-                                                           methyl                                                                  7890  "(3,4-      4-(1-                                                             methylenedioxyphenyl)                                                                     methyl)piperidinyl-                                                                      3-phenylpropyl                                         methyl"     methyl                                                      7891  2-thienylmethyl                                                                           "(3,4-     3-phenylpropyl                                                     methylenedioxyphenyl)                                                         methyl"                                                     7892  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          3-phenylpropyl                                   7893  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         3-phenylpropyl                                   7894  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        3-phenylpropyl                                   7895  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   3-phenylpropyl                                   7896  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  3-phenylpropyl                                   7897  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        3-phenylpropyl                                   7898  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       3-phenylpropyl                                   7899  2-methylbutyl                                                                             2-methylpropyl                                                                           3-phenylpropyl                                   7900  3-methylbutyl                                                                             2-methylbutyl                                                                            3-phenylpropyl                                   7901  cyclopropylmethyl                                                                         3-methylbutyl                                                                            3-phenylpropyl                                   7902  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        3-phenylpropyl                                   7903  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         3-phenylpropyl                                   7904  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        3-phenylpropyl                                   7905  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   3-phenylpropyl                                   7906  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      3-phenylpropyl                                   7907  "4-(N,N-    p-aminophenyl-methyl                                                                     3-phenylpropyl                                         dimethylamino)phenyl-                                                         methyl"                                                                 8073  benzyl      "4-(N,N-   2-(1-pyrolyl)ethyl                                                 dimethylamino)phenyl-                                                         methyl"                                                     8074  1-pyrolylmethyl                                                                           benzyl     2-(1-pyrolyl)ethyl                               8075  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          2-(1-pyrolyl)ethyl                               8076  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        2-(1-pyrolyl)ethyl                               8077  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       2-(1-pyrolyl)ethyl                               8078  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          2-(1-pyrolyl)ethyl                               8079  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        2-(1-pyrolyl)ethyl                               8080  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       2-(1-pyrolyl)ethyl                               8081  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          2-(1-pyrolyl)ethyl                               8082  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          2-(1-pyrolyl)ethyl                               8083  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          2-(1-pyrolyl)ethyl                               8084  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         2-(1-pyrolyl)ethyl                               8085  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         2-(1-pyrolyl)ethyl                               8086  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         2-(1-pyrolyl)ethyl                               8087  4-(1-       2-thiophenylmethyl                                                                       2-(1-pyrolyl)ethyl                                     methyl)piperidinyl-                                                           methyl                                                                  8088  "(3,4-      4-(1-      2-(1-pyrolyl)ethyl                                     methylenedioxyphenyl)                                                                     methyl)piperidinyl-                                               methyl"     methyl                                                      8089  2-thienylmethyl                                                                           "(3,4-     2-(1-pyrolyl)ethyl                                                 methylenedioxyphenyl)                                                         methyl"                                                     8090  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          2-(1-pyrolyl)ethyl                               8091  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         2-(1-pyrolyl)ethyl                               8092  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        2-(1-pyrolyl)ethyl                               8093  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   2-(1-pyrolyl)ethyl                               8094  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  2-(1-pyrolyl)ethyl                               8095  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        2-(1-pyrolyl)ethyl                               8096  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       2-(1-pyrolyl)ethyl                               8097  2-methylbutyl                                                                             2-methylpropyl                                                                           2-(1-pyrolyl)ethyl                               8098  3-methylbutyl                                                                             2-methylbutyl                                                                            2-(1-pyrolyl)ethyl                               8099  cyclopropylmethyl                                                                         3-methylbutyl                                                                            2-(1-pyrolyl)ethyl                               8100  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        2-(1-pyrolyl)ethyl                               8101  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         2-(1-pyrolyl)ethyl                               8102  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        2-(1-pyrolyl)ethyl                               8103  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   2-(1-pyrolyl)ethyl                               8104  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      2-(1-pyrolyl)ethyl                               8105  "4-(N,N-    p-aminophenyl-methyl                                                                     2-(1-pyrolyl)ethyl                                     dimethylamino)phenyl-                                                         methyl"                                                                 8106  benzyl      "4-(N,N-   2-(1-imidazoly)ethyl                                               dimethylamino(phenyl-                                                         methyl"                                                     8107  1-pyrolylmethyl                                                                           benzyl     2-(1-imidazolyl)ethyl                            8108  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          2-(1-imidazolyl)ethyl                            8109  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        2-(1-imidazolyl)ethyl                            8110  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       2-(1-imidazolyl)ethyl                            8111  1-triazolylmethyl                                                                         1-indolylmethyl                                                                          2-(1-imidazolyl)ethyl                            8112  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        2-(1-imidazolyl)ethyl                            8113  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       2-(1-imidazolyl)ethyl                            8114  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          2-(1-imidazolyl)ethyl                            8115  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          2-(1-imidazolyl)ethyl                            8116  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          2-(1-imidazolyl)ethyl                            8117  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         2-(1-imidazolyl)ethyl                            8118  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         2-(1-imidazolyl)ethyl                            8119  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         2-(1-imidazolyl)ethyl                            8120  4-(1-       2-thiophenylmethyl                                                                       2-(1-imidazolyl)ethyl                                  methyl)priperidinyl-                                                          methyl                                                                  8121  "(3,4-      4-(1-      2-(1-imidazolyl)ethyl                                  methylenedioxyphenyl)                                                                     methyl)piperidinyl-                                               methyl"     methyl                                                      8122  2-thienylmethyl                                                                           "(3,4-     2-(1-imidazolyl)ethyl                                              methylenedioxyphenyl)                                                         methyl"                                                     8123  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          2-(1-imidazolyl)ethyl                            8124  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         2-(1-imidazolyl)ethyl                            8125  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        2-(1-imidazolyl)ethyl                            8126  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   2-(1-imidazolyl)ethyl                            8127  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  2-(1-imidazolyl)ethyl                            8128  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        2-(1-imidazolyl)ethyl                            8129  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       2-(1-imidazolyl)ethyl                            8130  2-methylbutyl                                                                             2-methylpropyl                                                                           2-(1-imidazolyl)ethyl                            8131  3-methylbutyl                                                                             2-methylbutyl                                                                            2-(1-imidazolyl)ethyl                            8132  cyclopropylmethyl                                                                         3-methylbutyl                                                                            2-(1-imidazolyl)ethyl                            8133  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        2-(1-imidazolyl)ethyl                            8134  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         2-(1-imidazolyl)ethyl                            8135  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        2-(1-imidazolyl)ethyl                            8136  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   2-(1-imidazolyl)ethyl                            8137  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      2-(1-imidazolyl)ethyl                            8138  "4-(N,N-    p-aminophenyl-methyl                                                                     2-(1-imidazolyl)ethyl                                  dimethylamino)phenyl-                                                         methyl"                                                                 8139  benzyl      "4-(N,N-   2-pyridylmethyl                                                    dimethylamino)phenyl-                                                         methyl"                                                     8140  1-pyrolylmethyl                                                                           benzyl     2-pyridylmethyl                                  8141  1-pyrazolylmethyl                                                                         1-pyrolylmethyl                                                                          2-pyridylmethyl                                  8142  1-imidazolylmethyl                                                                        1-pyrazolylmethyl                                                                        2-pyridylmethyl                                  8143  1-indolylmethyl                                                                           1-imidazolylmethyl                                                                       2-pyridylmethyl                                  8144  1-trizolylmethyl                                                                          1-indolylmethyl                                                                          2-pyridylmethyl                                  8145  1-tetrazolylmethyl                                                                        1-triazolylmethyl                                                                        2-pyridylmethyl                                  8146  2-pyridylmethyl                                                                           1-tetrazolylmethyl                                                                       2-pyridylmethyl                                  8147  3-pyridylmethyl                                                                           2-pyridylmethyl                                                                          2-pyridylmethyl                                  8148  4-pyridylmethyl                                                                           3-pyridylmethyl                                                                          2-pyridylmethyl                                  8149  cyclohexylmethyl                                                                          4-pyridylmethyl                                                                          2-pyridylmethyl                                  8150  2-naphthylmethyl                                                                          cyclohexylmethyl                                                                         2-pyridylmethyl                                  8151  3-naphthylmethyl                                                                          2-naphthylmethyl                                                                         2-pyridylmethyl                                  8152  2-thiophenylmethyl                                                                        3-naphthylmethyl                                                                         2-pyridylmethyl                                  8153  4-(1-       2-thiophenylmethyl                                                                       2-pyridylmethyl                                        methyl)piperidinyl-                                                           methyl                                                                  8154  "(3,4-      4-(1-      2-pyridylmethyl                                        methylenedioxyphenyl)                                                                     methyl)piperidinyl-                                               methyl"     methyl                                                      8155  2-thienylmethyl                                                                           "(3,4-     2-pyridylmethyl                                                    methylenedioxyphenyl)                                                         methyl"                                                     8156  4-biphenylmethyl                                                                          2-thienylmethyl                                                                          2-pyridylmethyl                                  8157  pyrimidinylmethyl                                                                         4-biphenylmethyl                                                                         2-pyridylmethyl                                  8158  2-benzothiazolylmethyl                                                                    pyrimidinylmethyl                                                                        2-pyridylmethyl                                  8159  2-benzothiophenylmethyl                                                                   2-benzothiazolylmethyl                                                                   2-pyridylmethyl                                  8160  2-thiomethylethyl                                                                         2-benzothiophenylmethyl                                                                  2-pyridylmethyl                                  8161  2-thiomethylmethyl                                                                        2-thiomethylethyl                                                                        2-pyridylmethyl                                  8162  2-methylpropyl                                                                            2-thiomethylmethyl                                                                       2-pyridylmethyl                                  8163  2-methylbutyl                                                                             2-methylpropyl                                                                           2-pyridylmethyl                                  8164  3-methylbutyl                                                                             2-methylbutyl                                                                            2-pyridylmethyl                                  8165  cyclopropylmethyl                                                                         3-methylbutyl                                                                            2-pyridylmethyl                                  8166  cyclobutylmethyl                                                                          cyclopropylmethyl                                                                        2-pyridylmethyl                                  8167  cyclopentylmethyl                                                                         cyclobutylmethyl                                                                         2-pyridylmethyl                                  8168  p-hydroxyphenyl-methyl                                                                    cyclopentylmethyl                                                                        2-pyridylmethyl                                  8169  p-nitrophenylmethyl                                                                       p-hydroxyphenyl-methyl                                                                   2-pyridylmethyl                                  8170  p-aminophenyl-methyl                                                                      p-nitrophenylmethyl                                                                      2-pyridylmethyl                                  8171  "4-(N,N-    p-aminophenyl-methyl                                                                     2-pyridylmethyl                                        dimethylamino)phenyl-                                                         methyl"                                                                 __________________________________________________________________________

                                      TABLE 20                                    __________________________________________________________________________     ##STR110##                                                                   Ex.                                                                           No.                                                                              R4       R7       R22      R23                                             __________________________________________________________________________    8205                                                                             benzyl   benzyl   2-methallyl                                                                            2-methallyl                                     8206                                                                             1-pyrolylmethyl                                                                        1-pyrolylmethyl                                                                        4-methylpentyl                                                                         4-methylpentyl                                  8207                                                                             1-       1-       3-methallyl                                                                            3-methallyl                                        pyrazolylmethyl                                                                        pyrazolylmethyl                                                   8208                                                                             1-imidazolyl-                                                                          1-imidazolyl-                                                                          3-methylbutyl                                                                          3-methylbutyl                                      methyl   methyl                                                            8209                                                                             1-indolylmethyl                                                                        1-indolylmethyl                                                                        3-methylpentyl                                                                         3-methylpentyl                                  8210                                                                             2-pyridylmethyl                                                                        2-pyridylmethyl                                                                        3-pentyl 3-pentyl                                        8211                                                                             3-pyridylmethyl                                                                        3-pyridylmethyl                                                                        4-methylpentyl                                                                         4-methylpentyl                                  8212                                                                             4-pyridylmethyl                                                                        4-pyridylmethyl                                                                        "3,3-    "3,3-                                                                dimethallyl"                                                                           dimethallyl"                                    8213                                                                             cyclohexyl-                                                                            cyclohexylmethyl                                                                       "3,3-    "3,3-                                              methyl            dimethylbutyl"                                                                         dimethylbutyl"                                  8214                                                                             2-thiophenyl-                                                                          20-      allyl    allyl                                              methyl   thiophenylmethyl                                                  8215                                                                             "(3,4-   "(3,4-   cyclobutyl-                                                                            cyclobutyl-                                        methylene-                                                                             methylene-                                                                             methyl   methyl                                             dioxy-phenyl)-                                                                         dioxyphenyl)-                                                        methyl"  methyl"                                                           8216                                                                             2-thienylmethyl                                                                        2-thienylmethyl                                                                        cyclopropyl-                                                                           cyclopropyl-                                                         methyl   methyl                                          8217                                                                             4-       4-       isobutyl isobutyl                                           biphenylmethyl                                                                         biphenylmethyl                                                    8218                                                                             2-       2-       n-butyl  n-butyl                                            thiomethylethyl                                                                        thiomethylethyl                                                   8219                                                                             p-hydroxy-                                                                             p-hydroxy-                                                                             n-pentyl n-pentyl                                           phenylmethyl                                                                           phenylmethyl                                                      8220                                                                             p-nitrophenyl-                                                                         p-nitrophenyl-                                                                         propyl   propyl                                             methyl   methyl                                                            8221                                                                             benzyl   benzyl   2-methallyl                                                                            H                                               8222                                                                             1-pyrolylmethyl                                                                        1-pyrolylmethyl                                                                        4-methylpentyl                                                                         H                                               8223                                                                             1-       1-       3-methallyl                                                                            H                                                  pyrazolylmethyl                                                                        pyrazolylmethyl                                                   8224                                                                             1-imidazolyl-                                                                          1-imidazolyl-                                                                          3-methylbutyl                                                                          H                                                  methyl   methyl                                                            8225                                                                             1-indolylmethyl                                                                        1-indolylmethyl                                                                        3-methylpentyl                                                                         H                                               8226                                                                             2-pyridylmethyl                                                                        2-pyridylmethyl                                                                        3-pentyl H                                               8227                                                                             3-pyridylmethyl                                                                        3-pyridylmethyl                                                                        4-methylpentyl                                                                         H                                               8228                                                                             4-pyridylmethyl                                                                        4-pyridylmethyl                                                                        "3,3-    H                                                                    dimethallyl"                                             8229                                                                             cyclohexyl-                                                                            cyclohexyl-                                                                            "3,3-    H                                                  methyl   methyl   dimethylbutyl"                                           8230                                                                             2-thiophenyl-                                                                          2-thiophenyl-                                                                          allyl    H                                                  methyl   methyl                                                            8231                                                                             "(3,4-   "(3,4-   cyclobutyl-                                                                            H                                                  methylenedioxy-                                                                        methylenedioxy-                                                                        methyl                                                      phenyl)methyl"                                                                         phenyl)methyl"                                                    8232                                                                             2-thienylmethyl                                                                        2-thienylmethyl                                                                        cyclopropyl-                                                                           H                                                                    methyl                                                   8233                                                                             4-       4-       isobutyl H                                                  biphenylmethyl                                                                         biphenylmethyl                                                    8234                                                                             2-       2-       n-butyl                                                     thiomethylethyl                                                                        thiomethylethyl                                                   8235                                                                             p-       p-       n-pentyl H                                                  hydroxyphenyl-                                                                         hydroxyphenyl-                                                       methyl   methyl                                                            8236                                                                             p-nitrophenyl-                                                                         p-nitrophenyl                                                                          propyl   H                                                  methyl   methyl                                                            8237                                                                             benzyl   p-nitrophenyl-                                                                         2-methallyl                                                                            2-methallyl                                                 methyl                                                            8238                                                                             1-pyrolylmethyl                                                                        benzyl   4-methylpentyl                                                                         4-methylpentyl                                  8239                                                                             1-       1-pyrolylmethyl                                                                        3-methallyl                                                                            3-methallyl                                        pyrazolylmethyl                                                            8240                                                                             1-imidazolyl-                                                                          1-       3-methylbutyl                                                                          3-methylbutyl                                      methyl   pyrazolylmethyl                                                   8241                                                                             1-indolylmethyl                                                                        1-       3-methylpentyl                                                                         3-methylpentyl                                              imidazolylmethyl                                                  8242                                                                             2-pyridylmethyl                                                                        1-indolylmethyl                                                                        3-pentyl 3-pentyl                                        8243                                                                             3-pyridylmethyl                                                                        2-pyridylmethyl                                                                        4-methylpentyl                                                                         4-methylpentyl                                  8244                                                                             4-pyridylmethyl                                                                        3-pyridylmethyl                                                                        "3,3-    "3,3-                                                                dimethallyl"                                                                           dimethallyl"                                    8245                                                                             cyclohexylmethyl                                                                       4-pyridylmethyl                                                                        "3,3-    "3,3-                                                                dimethylbutyl"                                                                         dimethylbutyl"                                  8246                                                                             2-thiophenyl-                                                                          cyclohexyl-                                                                            allyl    allyl                                              methyl   methyl                                                            8247                                                                             "(3,4-   2-thiophenyl-                                                                          cyclobutylmethyl                                                                       cyclobutylmethyl                                   methylenedioxy-                                                                        methyl                                                               phenyl)methyl"                                                             8248                                                                             2-thienylmethyl                                                                        "(3,4-   cyclopropylmethyl                                                                      cyclopropylmethyl                                           methylenedioxy-                                                               phenyl)methyl"                                                    8249                                                                             4-       2-thienylmethyl                                                                        isobutyl isobutyl                                           biphenylmethyl                                                             8250                                                                             2-       4-       n-butyl  n-butyl                                            thiomethylethyl                                                                        biphenylmethyl                                                    8251                                                                             p-       2-       n-pentyl n-pentyl                                           hydroxyphenyl-                                                                         thiomethylethyl                                                      methyl                                                                     8252                                                                             p-nitrophenyl-                                                                         p-       propyl   propyl                                             methyl   hydroxyphenyl-                                                                methyl                                                            8253                                                                             benzyl   p-nitrophenyl-                                                                         2-methallyl                                                                            2-methallyl                                                 methyl                                                            8254                                                                             1-pyrolylmethyl                                                                        benzyl   4-methylpentyl                                                                         4-methylpentyl                                  8255                                                                             1-       1-pyrolylmethyl                                                                        3-methallyl                                                                            3-methallyl                                        pyrazolylmethyl                                                            8256                                                                             1-imidazolyl-                                                                          1-       3-methylbutyl                                                                          3-methylbutyl                                      methyl   pyrazolylmethyl                                                   8257                                                                             1-indolylmethyl                                                                        1-imidazolyl-                                                                          3-methylpentyl                                                                         3-methylpentyl                                              methyl                                                            8258                                                                             2-pyridylmethyl                                                                        1-indolylmethyl                                                                        3-pentyl 3-pentyl                                        8259                                                                             3-pyridylmethyl                                                                        2-pyridylmethyl                                                                        4-methylpentyl                                                                         4-methylpentyl                                  8260                                                                             4-pyridylmethyl                                                                        3-pyridylmethyl                                                                        "3,3-    "3,3-                                                                dimethallyl"                                                                           dimethallyl"                                    8261                                                                             cyclohexylmethyl                                                                       4-pyridylmethyl                                                                        "3,3-    "3,3-                                                                dimethylbutyl"                                                                         dimethylbutyl"                                  8262                                                                             2-thiophenyl-                                                                          cyclohexylmethyl                                                                       allyl    allyl                                              methyl                                                                     8263                                                                             "(3,4-   2-       cyclobutylmethyl                                                                       cyclobutylmethyl                                   methylenedioxy-                                                                        thiophenylmethyl                                                     phenyl)methyl"                                                             8264                                                                             2-thienylmethyl                                                                        "(3,4-   cyclopropyl-                                                                           cyclopropyl-                                                methylenedioxy-                                                                        methyl   methyl                                                      phenyl)methyl"                                                    8265                                                                             4-       2-thienylmethyl                                                                        isobutyl isobutyl                                           biphenylmethyl                                                             8266                                                                             2-       4-       n-butyl  n-butyl                                            thiomethylethyl                                                                        biphenylmethyl                                                    8267                                                                             p-       2-       n-pentyl n-pentyl                                           hydroxyphenyl-                                                                         thiomethylethyl                                                      methyl                                                                     8268                                                                             p-nitrophenyl-                                                                         p-       propyl   propyl                                             methyl   hydroxyphenyl-                                                                methyl                                                            8269                                                                             benzyl   p-nitrophenyl-                                                                         2-methallyl                                                                            propyl                                                      methyl                                                            8270                                                                             1-pyrolylmethyl                                                                        benzyl   4-methylpentyl                                                                         2-methallyl                                     8271                                                                             1-       1-pyrolylmethyl                                                                        3-methallyl                                                                            4-methylpentyl                                     pyrazolylmethyl                                                            8272                                                                             1-imidazolyl-                                                                          1-       3-methylbutyl                                                                          3-methallyl                                        methyl   pyrazolylmethyl                                                   8273                                                                             1-indolylmethyl                                                                        1-imidazolyl-                                                                          3-methylpentyl                                                                         3-methylbutyl                                               methyl                                                            8274                                                                             2-pyridylmethyl                                                                        1-indolylmethyl                                                                        3-pentyl 3-methylpentyl                                  8275                                                                             3-pyridylmethyl                                                                        2-pyridylmethyl                                                                        4-methylpentyl                                                                         3-pentyl                                        8276                                                                             4-pyridylmethyl                                                                        3-pyridylmethyl                                                                        "3,3-    4-methylpentyl                                                       dimethallyl"                                             8277                                                                             cyclohexylmethyl                                                                       4-pyridylmethyl                                                                        "3,3-    "3,3-                                                                dimethylbutyl"                                                                         dimethallyl"                                    8278                                                                             2-thiophenyl-                                                                          cyclohexyl-                                                                            allyl    "3,3-                                              methyl   methyl            dimethylbutyl"                                  8279                                                                             "(3,4-   2-       cyclobutyl-                                                                            allyl                                              methylenedioxy-                                                                        thiophenylmethyl                                                                       methyl                                                      phenyl)methyl"                                                             8280                                                                             2-thienylmethyl                                                                        "(3,4-   cyclopropyl-                                                                           cyclobutylmethyl                                            methylenedioxy-                                                                        methyl                                                               phenyl)methyl"                                                    8281                                                                             4-       2-thienylmethyl                                                                        isobutyl cyclopropyl-                                       biphenylmethyl             methyl                                          8282                                                                             2-       4-       n-butyl  isobutyl                                           thiomethylethyl                                                                        biphenylmethyl                                                    8283                                                                             p-       2-       n-pentyl n-butyl                                            hydroxyphenyl-                                                                         thiomethylethyl                                                      methyl                                                                     8284                                                                             p-nitrophenyl-                                                                         p-       propyl   n-pentyl                                           methyl   hydroxyphenyl-                                                                methyl                                                            __________________________________________________________________________

                                      TABLE 21                                    __________________________________________________________________________     ##STR111##                                                                   Ex.                                                                           No.                                                                              R.sup.22   R.sup.23   R.sup.4 = R.sup.7                                    __________________________________________________________________________    8285                                                                             (m-hydroxymethyl)                                                                        (m-tetrazolyl)benzyl                                                                     benzyl                                                  benzyl                                                                     8286                                                                             (p-hydroxymethyl)benzyl                                                                  (m-tetrazolyl)benzyl                                                                     benzyl                                               8287                                                                             (m-hydroxy)benzyl                                                                        (m-tetrazolyl)benzyl                                                                     benzyl                                               8288                                                                             (p-hydroxy)benzyl                                                                        (m-tetrazolyl)benzyl                                                                     benzyl                                               8289                                                                             (m-carboxamido)benzyl                                                                    (m-tetrazolyl)benzyl                                                                     benzyl                                               8290                                                                             (m-(N-methyl                                                                             (m-tetrazolyl)benzyl                                                                     benzyl                                                  carboxamido))benzyl                                                        8291                                                                             (m-hydroxymethyl)                                                                        (m-imidazolyl)benzyl                                                                     benzyl                                                  benzyl                                                                     8292                                                                             (p-hydroxymethyl)benzyl                                                                  (m-imidazolyl)benzyl                                                                     benzyl                                               8293                                                                             (m-hydroxy)benzyl                                                                        (m-imidazolyl)benzyl                                                                     benzyl                                               8294                                                                             (p-hydroxy)benzyl                                                                        (m-imidazolyl)benzyl                                                                     benzyl                                               8295                                                                             (m-carboxamido)benzyl                                                                    (m-imidazolyl)benzyl                                                                     benzyl                                               8296                                                                             (m-(N-methyl                                                                             (m-imidazolyl)benzyl                                                                     benzyl                                                  carboxamido))benzyl                                                        8297                                                                             (m-hydroxymethyl)                                                                        (m-tetrazolyl)benzyl                                                                     (p-fluoro)benzyl                                        benzyl                                                                     8298                                                                             (p-hydroxymethyl)benzyl                                                                  (m-tetrazolyl)benzyl                                                                     (p-fluoro)benzyl                                     8299                                                                             (m-hydroxy)benzyl                                                                        (m-tetrazolyl)benzyl                                                                     (p-fluoro)benzyl                                     8300                                                                             (p-hydroxy)benzyl                                                                        (m-tetrazolyl)benzyl                                                                     (p-fluoro)benzyl                                     8301                                                                             (m-carboxamido)benzyl                                                                    (m-tetrazolyl)benzyl                                                                     (p-fluoro)-benzyl                                    8302                                                                             (m-(N-methyl                                                                             (m-tetrazolyl)benzyl                                                                     (p-fluoro)benzyl                                        carboxamido))benzyl                                                        8303                                                                             (m-hydroxymethyl)                                                                        (m-imidazolyl)benzyl                                                                     (p-fluoro)benzyl                                        benzyl                                                                     8304                                                                             (p-hydroxymethyl)benzyl                                                                  (m-imidazolyl)benzyl                                                                     (p-fluoro)benzyl                                     8305                                                                             (m-hydroxy)benzyl                                                                        (m-imidazolyl)benzyl                                                                     (p-fluoro)benzyl                                     8306                                                                             (p-hydroxy)benzyl                                                                        (m-imidazolyl)benzyl                                                                     (p-fluoro)benzyl                                     8307                                                                             (m-carboxamido)benzyl                                                                    (m-imidazolyl)benzyl                                                                     (p-fluoro)benzyl                                     8308                                                                             (m-(N-methyl                                                                             (m-imidazolyl)benzyl                                                                     (p-fluoro)benzyl                                        carboxamido))benzyl                                                        8309                                                                             (m-carboxy)benzyl                                                                        (m-hydroxy)benzyl                                                                        benzyl                                               8310                                                                             (m-carboxy)benzyl                                                                        (p-hydroxy)benzyl                                                                        benzyl                                               8311                                                                             (m-carboxy)benzyl                                                                        (m-hydroxymethyl)                                                                        benzyl                                                             benzyl                                                          8312                                                                             (m-carboxy)benzyl                                                                        (p-hydroxymethyl)                                                                        benzyl                                                             benzyl                                                          8313                                                                             (m-carboxy)benzyl                                                                        (m-carboxamido)                                                                          benzy;l                                                            benzyl                                                          8314                                                                             (m-carboxy)benzyl                                                                        (m-(N-methyl                                                                             benzyl                                                             carboxamido))benzyl                                             8315                                                                             (m-carboxy)benzyl                                                                        (m-acetyl)benzyl                                                                         benzyl                                               8316                                                                             (m-carboxy)benzyl                                                                        (m-glycolyl)benzyl                                                                       benzyl                                               8317                                                                             (m-carboxy)benzyl                                                                        (m-sulfoamido)                                                                           benzyl                                                             benzyl                                                          8318                                                                             (m-carboxy)benzyl                                                                        (m-(N-methylamino)                                                                       benzyl                                                             benzyl                                                          8319                                                                             (m-carboxamido)benzyl                                                                    (m-hydroxy)benzyl                                                                        benzyl                                               8320                                                                             (m-carboxamido)benzyl                                                                    (p-hydroxy)benzyl                                                                        benzyl                                               8321                                                                             (m-carboxamido)benzyl                                                                    (m-hydroxymethyl)                                                                        benzyl                                                             benzyl                                                          8322                                                                             (m-carboxamido)benzyl                                                                    (p-hydroxymethyl)                                                                        benzyl                                                             benzyl                                                          8323                                                                             (m-carboxamido)benzyl                                                                    (m-carboxamido)                                                                          benzyl                                                             benzyl                                                          8324                                                                             (m-carboxamido)benzyl                                                                    (m-(N-methyl                                                                             benzyl                                                             carboxamido))benzyl                                             8325                                                                             (m-carboxamido)benzyl                                                                    (m-acetyl)benzyl                                                                         benzyl                                               8326                                                                             (m-carboxamido)benzyl                                                                    (m-glycolyl)benzyl                                                                       benzyl                                               8327                                                                             (m-carboxamido)benzyl                                                                    (m-sulfoamido)                                                                           benzyl                                                             benzyl                                                          8328                                                                             (m-carboxamido)benzyl                                                                    (m-(N-methylamino)                                                                       benzyl                                                             benzyl                                                          8329                                                                             (m-(N-methyl                                                                             (m-hydroxy)benzyl                                                                        benzyl                                                  carboxamido))benzyl                                                        8330                                                                             (m-(N-methyl                                                                             (p-hydroxy)benzyl                                                                        benzyl                                                  carboxamido))benzyl                                                        8331                                                                             (m-(N-methyl                                                                             (m-hydroxymethyl)                                                                        benzyl                                                  carboxamido))benzyl                                                                      benzyl                                                          8332                                                                             (m-(N-methyl                                                                             (p-hydroxymethyl)                                                                        benzyl                                                  carboxamido))benzyl                                                                      benzyl                                                          8333                                                                             (m-(N-methyl                                                                             (m-carboxamido)                                                                          benzyl                                                  carboxamido))benzyl                                                                      benzyl                                                          8334                                                                             (m-(N-methyl                                                                             (m-(N-methyl                                                                             benzyl                                                  carboxamido))benzyl                                                                      carboxamido))benzyl                                             8335                                                                             (m-(N-methyl                                                                             (m-acetyl)benzyl                                                                         benzyl                                                  carboxamido))benzyl                                                        8336                                                                             (m-(N-methyl                                                                             (m-glycolyl)benzyl                                                                       benzyl                                                  carboxamido))benzyl                                                        8337                                                                             (m-(N-methyl                                                                             (m-sulfoamido)                                                                           benzyl                                                  carboxamido))benzyl                                                                      benzyl                                                          8338                                                                             (m-(N-methyl                                                                             (m-(N-methylamino)                                                                       benzyl                                                  carboxamido))benzyl                                                                      benzyl                                                          8339                                                                             (m-sulfonamido)benzyl                                                                    (m-hydroxy)benzyl                                                                        benzyl                                               8340                                                                             (m-sulfonamido)benzyl                                                                    (p-hydroxy)benzyl                                                                        benzyl                                               8341                                                                             (m-sulfonamido)benzyl                                                                    (m-hydroxymethyl)                                                                        benzyl                                                             benzyl                                                          8342                                                                             (m-sulfonamido)benzyl                                                                    (p-hydroxymethyl)                                                                        benzyl                                                             benzyl                                                          8343                                                                             (m-sulfonamido)benzyl                                                                    (m-carboxamido)                                                                          benzyl                                                             benzyl                                                          8344                                                                             (m-sulfonamido)benzyl                                                                    (m-(N-methyl                                                                             benzyl                                                             carboxamido))benzyl                                             8345                                                                             (m-sulfonamido)benzyl                                                                    (m-acetyl)benzyl                                                                         benzyl                                               8346                                                                             (m-sulfonamido)benzyl                                                                    (m-glycolyl)benzyl                                                                       benzyl                                               8347                                                                             (m-sulfonamido)benzyl                                                                    (m-sulfonamido)                                                                          benzyl                                                             benzyl                                                          8348                                                                             (m-sulfonamido)benzyl                                                                    (m-(N-methylamino)                                                                       benzyl                                                             benzyl                                                          8349                                                                             m-(N-ethylcarboxamido)                                                                   (m-hydroxy)benzyl                                                                        benzyl                                                  benzyl                                                                     8350                                                                             m-(N-ethylcarboxamido)                                                                   (p-hydroxy)benzyl                                                                        benzyl                                                  benzyl                                                                     8351                                                                             m-(N-ethylcarboxamido)                                                                   (m-hydroxymethyl)                                                                        benzyl                                                  benzyl     benzyl                                                          8352                                                                             m-(N-ethylcarboxamido)                                                                   (p-hydroxymethyl)                                                                        benzyl                                                  benzyl     benzyl                                                          8353                                                                             m-(N-ethylcarboxamido)                                                                   (m-carboxamido)                                                                          benzyl                                                  benzyl     benzyl                                                          8354                                                                             m-(N-ethylcarboxamido)                                                                   (m-(N-methyl                                                                             benzyl                                                  benzyl     carboxamido))benzyl                                             8355                                                                             m-(N-ethylcarboxamido)                                                                   (m-acetyl)benzyl                                                                         benzyl                                                  benzyl                                                                     8356                                                                             m-(N-ethylcarboxamido)                                                                   (m-glycolyl)benzyl                                                                       benzyl                                                  benzyl                                                                     8357                                                                             m-(N-ethylcarboxamido)                                                                   (m-sulfonamido)                                                                          benzyl                                                  benzyl     benzyl                                                          8358                                                                             m-(N-ethylcarboxamido)                                                                   (m-(N-methylamino)                                                                       benzyl                                                  benzyl     benzyl                                                          8359                                                                             3-pyridylmethyl                                                                          (m-hydroxy)benzyl                                                                        benzyl                                               8360                                                                             3-pyridylmethyl                                                                          (p-hydroxy)benzyl                                                                        benzyl                                               8361                                                                             3-pyridylmethyl                                                                          (m-hydroxymethyl)                                                                        benzyl                                                             benzyl                                                          8362                                                                             3-pyridylmethyl                                                                          (p-hydroxymethyl)                                                                        benzyl                                                             benzyl                                                          8363                                                                             3-pyridylmethyl                                                                          (m-carboxamido)                                                                          benzyl                                                             benzyl                                                          8364                                                                             3-pyridylmethyl                                                                          (m-(N-methyl                                                                             benzyl                                                             carboxamido))benzyl                                             8365                                                                             3-pyridylmethyl                                                                          (m-acetyl)benzyl                                                                         benzyl                                               8366                                                                             3-pyridylmethyl                                                                          (m-glycolyl)benzyl                                                                       benzyl                                               8367                                                                             3-pyridylmethyl                                                                          (m-sulfonamido)                                                                          benzyl                                                             benzyl                                                          8368                                                                             3-pyridylmethyl                                                                          (m-(N-methylamino)                                                                       benzyl                                                             benzyl                                                          8369                                                                             (m-carboxy)benzyl                                                                        (m-hydroxy)benzyl                                                                        (p-fluoro)benzyl                                     8370                                                                             (m-carboxy)benzyl                                                                        (p-hydroxy)benzyl                                                                        (p-fluoro)benzyl                                     8371                                                                             (m-carboxy)benzyl                                                                        (m-hydroxymethyl)                                                                        (p-fluoro)benzyl                                                   benzyl                                                          8372                                                                             (m-carboxy)benzyl                                                                        (p-hydroxymethyl)                                                                        (p-fluoro)benzyl                                                   benzyl                                                          8373                                                                             (m-carboxy)benzyl                                                                        (m-carboxamido)                                                                          (p-fluoro)benzyl                                                   benzyl                                                          8374                                                                             (m-carboxy)benzyl                                                                        (m-(N-methyl                                                                             (p-fluoro)benzyl                                                   carboxamido))benzyl                                             8375                                                                             (m-carboxy)benzyl                                                                        (m-acetyl)benzyl                                                                         (p-fluoro)benzyl                                     8376                                                                             (m-carboxy)benzyl                                                                        (m-glycolyl)benzyl                                                                       (p-fluoro)benzyl                                     8377                                                                             (m-carboxy)benzyl                                                                        (m-sulfonamido)                                                                          (p-fluoro)benzyl                                                   benzyl                                                          8378                                                                             (m-carboxy)benzyl                                                                        (m-(N-methylamino)                                                                       (p-fluoro)benzyl                                                   benzyl                                                          8379                                                                             (m-carboxamido)benzyl                                                                    (m-hydroxy)benzyl                                                                        (p-fluoro)benzyl                                     8380                                                                             (m-carboxamido)benzyl                                                                    (p-hydroxy)benzyl                                                                        (p-fluoro)benzyl                                     8381                                                                             (m-carboxamido)benzyl                                                                    (m-hydroxymethyl)                                                                        (p-fluoro)benzyl                                                   benzyl                                                          8382                                                                             (m-carboxamido)benzyl                                                                    (p-hydroxymethyl)                                                                        (p-fluoro)benzyl                                                   benzyl                                                          8383                                                                             (m-carboxamido)benzyl                                                                    (m-carboxamido)                                                                          (p-fluoro)benzyl                                                   benzyl                                                          8384                                                                             (m-carboxamido)benzyl                                                                    (m-(N-methyl                                                                             (p-fluoro)benzyl                                                   carboxamido))benzyl                                             8385                                                                             (m-carboxamido)benzyl                                                                    (m-acetyl)benzyl                                                                         (p-fluoro)benzyl                                     8386                                                                             (m-carboxamido)benzyl                                                                    (m-glycolyl)benzyl                                                                       (p-fluoro)benzyl                                     8387                                                                             (m-carboxamido)benzyl                                                                    (m-sulfonamido)                                                                          (p-fluoro)benzyl                                                   benzyl                                                          8388                                                                             (m-carboxamido)benzyl                                                                    (m-(N-methylamino)                                                                       (p-fluoro)benzyl                                                   benzyl                                                          8389                                                                             (m-(N-methyl                                                                             (m-hydroxy)benzyl                                                                        (p-fluoro)benzyl                                        carboxamido))benzyl                                                        8390                                                                             (m-N-methyl                                                                              (p-hydroxy)benzyl                                                                        (p-fluoro)benzyl                                        carboxamido))benzyl                                                        8391                                                                             (m-(N-methyl                                                                             (m-hydroxymethyl)                                                                        (p-fluoro)benzyl                                        carboxamido))benzyl                                                                      benzyl                                                          8392                                                                             (m-(N-methyl                                                                             (p-hydroxymethyl)                                                                        (p-fluoro)benzyl                                        carboxamido))benzyl                                                                      benzyl                                                          8393                                                                             (m-(N-methyl                                                                             (m-carboxamido)                                                                          (p-fluoro)benzyl                                        carboxamido))benzyl                                                                      benzyl                                                          8394                                                                             (m-(N-methyl                                                                             (m-(N-methyl                                                                             (p-fluoro)benzyl                                        carboxamido))benzyl                                                                      carboxamido))benzyl                                             8395                                                                             (m-(N-methyl                                                                             (m-acetyl)benzyl                                                                         (p-fluoro)benzyl                                        carboxamido))benzyl                                                        8396                                                                             (m-(N-methyl                                                                             (m-glycolyl)benzyl                                                                       (p-fluoro)benzyl                                        carboxamido))benzyl                                                        8397                                                                             (m-(N-methyl                                                                             (m-sulfonamido)                                                                          (p-fluoro)benzyl                                        carboxamido))benzyl                                                                      benzyl                                                          8398                                                                             (m-(N-methyl                                                                             (m-N-methylamino)                                                                        (p-fluoro)benzyl                                        carboxamido))benzyl                                                                      benzyl                                                          8399                                                                             (m-sulfonamido)benzyl                                                                    (m-hydroxy)benzyl                                                                        (p-fluoro)benzyl                                     8400                                                                             (m-sulfonamido)benzyl                                                                    (p-hydroxy)benzyl                                                                        (p-fluoro)benzyl                                     8401                                                                             (m-sulfonamido)benzyl                                                                    (m-hydroxymethyl)                                                                        (p-fluoro)benzyl                                                   benzyl                                                          8402                                                                             (m-sulfonamido)benzyl                                                                    (p-hydroxymethyl)                                                                        (p-fluoro)benzyl                                                   benzyl                                                          8403                                                                             (m-sulfonamido)benzyl                                                                    (m-carboxamido)                                                                          (p-fluoro)benzyl                                                   benzyl                                                          8404                                                                             (m-sulfonamido)benzyl                                                                    (m-(N-methyl                                                                             (p-fluoro)benzyl                                                   carboxamido))benzyl                                             8405                                                                             (m-sulfonamido)benzyl                                                                    (m-acetyl)benzyl                                                                         (p-fluoro)benzyl                                     8406                                                                             (m-sulfonamido)benzyl                                                                    (m-glycolyl)benzyl                                                                       (p-fluoro)benzyl                                     8407                                                                             (m-sulfonamido)benzyl                                                                    (m-sulfonamido)                                                                          (p-fluoro)benzyl                                                   benzyl                                                          8408                                                                             (m-sulfonamido)benzyl                                                                    (m-(N-methylamino)                                                                       (p-fluoro)benzyl                                                   benzyl                                                          8409                                                                             m-(N-ethylcarboxamido)                                                                   (m-hydroxy)benzyl                                                                        (p-fluoro)benzyl                                        benzyl                                                                     8410                                                                             m-(N-ethylcarboxamido)                                                                   (p-hydroxy)benzyl                                                                        (p-fluoro)benzyl                                        benzyl                                                                     8411                                                                             m-(N-ethylcarboxamido)                                                                   (m-hydroxymethyl)                                                                        (p-fluoro)benzyl                                        benzyl     benzyl                                                          5747                                                                             m-(N-ethylcarboxamido)                                                                   (p-hydroxymethyl)                                                                        (p-fluoro)benzyl                                        benzyl     benzyl                                                          5748                                                                             m-(N-ethylcarboxamido)                                                                   (m-carboxamido)                                                                          (p-fluoro)benzyl                                        benzyl     benzyl                                                          5749                                                                             m-(N-ethylcarboxamido)                                                                   (m-(N-methyl                                                                             (p-fluoro)benzyl                                        benzyl     carboxamido))benzyl                                             5750                                                                             m-(N-ethylcarboxamido)                                                                   (m-acetyl)benzyl                                                                         (p-fluoro)benzyl                                        benzyl                                                                     5751                                                                             m-(N-ethylcarboxamido)                                                                   (m-glycolyl)benzyl                                                                       (p-fluoro)benzyl                                        benzyl                                                                     5752                                                                             m-(N-ethylcarboxamido)                                                                   (m-sulfonamido)                                                                          (p-fluoro)benzyl                                        benzyl     benzyl                                                          5753                                                                             m-(N-ethylcarboxamido)                                                                   (m-(N-methylamino)                                                                       (p-fluoro)benzyl                                        benzyl     benzyl                                                          5754                                                                             3-pyridylmethyl                                                                          (m-hydroxy)benzyl                                                                        (p-fluoro)benzyl                                     5755                                                                             3-pyridylmethyl                                                                          (p-hydroxy)benzyl                                                                        (p-fluoro)benzyl                                     5756                                                                             3-pyridylmethyl                                                                          (m-hydroxymethyl)                                                                        (p-fluoro)benzyl                                                   benzyl                                                          5757                                                                             3-pyridylmethyl                                                                          (p-hydroxymethyl)                                                                        (p-fluoro)benzyl                                                   benzyl                                                          5758                                                                             3-pyridylmethyl                                                                          (m-carboxamido)                                                                          (p-fluoro)benzyl                                                   benzyl                                                          5759                                                                             3-pyridylmethyl                                                                          (m-(N-methyl                                                                             (p-fluoro)benzyl                                                   carboxamido))benzyl                                             5760                                                                             3-pyridylmethyl                                                                          (m-acetyl)benzyl                                                                         (p-fluoro)benzyl                                     5761                                                                             3-pyridylmethyl                                                                          (m-glycolyl)benzyl                                                                       (p-fluoro)benzyl                                     5762                                                                             3-pyridylmethyl                                                                          (m-sulfonamido)                                                                          (p-fluoro)benzyl                                                   benzyl                                                          5763                                                                             3-pyridylmethyl                                                                          (m-(N-methylamino)                                                                       (p-fluoro)benzyl                                                   benzyl                                                          __________________________________________________________________________

What is claimed is:
 1. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of formula (I): ##STR112## or a pharmaceuticallyacceptable salt form thereof wherein: R⁴ and R⁷ are independentlyselected from the following groups:hydrogen; C₁ -C₈ alkyl substitutedwith 0-3 R¹¹ ; C₂ -C₈ alkenyl substituted with 0-3 R¹¹ ; C₂ -C₈ alkynylsubstituted with 0-3 R¹¹ ; a C₃ -C₁₄ carbocyclic ring system substitutedwith 0-3 R¹¹ or 0-3 R¹² ; a heterocyclic ring selected independentlyfrom indolyl, furanyl, pyridyl, thienyl, pyrrolyl, benzo b!thienyl,pyrazolyl, thiazolyl, benzofuranyl, tetrahydroisoquinolinyl,benzotriazolyl, benzimidazolyl, or imidazolyl, said heterocyclic ringsystem being substituted with 0-2 R¹² ; --CO₂ R¹³ ; R^(4A) and R^(7A)are independently selected from the following groups:hydrogen; C₁ -C₄alkyl substituted with 0-6 halogen or 0-3 C₁ -C₂ alkoxy; benzylsubstituted with 0-6 halogen or 0-3 C₁ -C₂ alkoxy; --CO₂ R¹³ ; R⁴ andR^(4A) can alternatively join to form a 5-7 membered carbocyclic ringsubstituted with 0-2 R¹² ; R⁷ and R^(7A) can alternatively join to forma 5-7 membered carbocyclic ring substituted with 0-2 R¹² ; n is 1; R⁵ isselected from H; halogen; --N(R²⁰)₂, --SR²⁰, --OR²⁰, --N₃ or C₁ -C₆alkyl substituted with 0-3 R¹¹ ; R⁶ is independently selected from:hydrogen, halogen, --N(R²⁰)₂, --SR²⁰, --OR²¹, --N₃ or C₁ -C₆ alkylsubstituted with 0-3 R¹¹ ; R⁵ and R⁶ can alternatively join to form anepoxide or aziridine ring; --OCH₂ SCH₂ O--; --OC(═O)O--; --OCH₂ O--;--OC(═S)O--; --OC(═O)C(═O)O--; --OC(CH₃)₂ O--; --OC((CH₂)₃ NH₂)(CH₃)O--;--OC(OCH₃)(CH₂ CH₂ CH₃)O--; --OS(═O)O--; --NHC(═O)NH--; --OC(═O)NH--;--NHC(═O)O--; --NHCH₂ O--; --OCH₂ NH--; --NHC(═S)O--; --OS(═O)NH--;--NHC(═O)C(═O)O--; --OC(═O)C(═O)NH--; --NHC(═O)C(═O)NH--; --NHC(CH₃)₂O--; or --OC(CH₃)₂ NH--; R^(5a) is selected from hydrogen, halogen, C₁-C₆ alkyl, --N(R²⁰)₂, --SR²⁰, or --OR²⁰ ; R^(6a) is selected from:hydrogen, halogen, C₁ -C₆ alkyl, --N(R²⁰)₂, --SR²⁰ or --OR²¹ ; R⁵ andR^(5a) can alternatively join to form ═O, ═S, or a ketal ring; R⁶ andR^(6a) can alternatively join to form ═O, ═S, or a ketal ring; R²⁰ andR²¹ are independently selected from:hydrogen; C₁ -C₆ alkyl substitutedwith 0-3 R¹¹ ; C₃ -C₆ alkoxyalkyl substituted with 0-3 R¹¹ ; C₁ -C₆alkylcarbonyl substituted with 0-3 R¹¹ ; C₁ -C₆ alkoxycarbonylsubstituted with 0-3 R¹¹ ; C₁ -C₆ alkylaminocarbonyl substituted with0-3 R¹¹ ; benzoyl substituted with 0-3 R¹² ; phenoxycarbonyl substitutedwith 0-3 R¹² ; phenylaminocarbonyl substituted with 0-3 R¹² ; orphosphate ester; R¹¹ is selected from one or more of the following:H,keto, halogen, cyano, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, --CO₂ R¹³,--OC(═O)R¹³, --OR¹³, --S(O)_(m) R¹³, --NHC(═NH)NHR¹³, --C(═NH)NHR¹³,--C(═O)NR¹³ R¹⁴, --NR¹⁴ C(═O)R¹³, ═NOR¹⁴, --NR¹⁴ C(═O)OR¹⁴, --OC(═O)NR¹³R¹⁴, --NR¹³ C(═O)NR¹³ R¹⁴, --NR¹⁴ SO₂ NR¹³ R¹⁴, --NR¹⁴ SO₂ R¹³, --SO₂NR¹³ R¹⁴, --OP(O)(OR¹³)₂, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₃ -C₆cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C₇ -C₁₀arylalkyl, hydroxamic acid, hydrazide, boronic acid, sulfonamide,formyl, C₃ -C₆ cycloalkoxy, C₁ -C₄ alkyl substituted with --NR¹³ R¹⁴, C₁-C₄ hydroxyalkyl, methylenedioxy, ethylenedioxy, C₁ -C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁ -C₄ alkoxycarbonyl, pyridylcarbonyloxy, C₁ -C₄alkylcarbonyl, C₁ -C₄ alkylcarbonylamino, --OCH₂ CO₂ H,2-(1-morpholino)ethoxy, azido, or --C(R¹⁴)═N(OR¹⁴); - 3amino acidslinked together via amide bonds, said amino acid being linked via theamine or carboxylate terminus; C₃ -C₁₀ cycloalkyl substituted with 0-2R¹² ; C₁ -C₄ alkyl substitued with 0-2 R¹² aryl(C₁ -C₃ alkyl)-,substituted with 0-2 R¹² ; C₂ -C₆ alkoxyalkyl-, substituted with 0-2 R¹²; C₁ -C₄ alkylcarbonyloxy substituted with 0-2 R¹², C₆ -C₁₀arylcarbonyloxy substituted with 0-2 R¹², a C₅ -C₁₄ carbocyclic residuesubstituted with 0-3 R¹² ; a 5- to 10-membered heterocyclic ring systemcontaining 1 to 4 heteroatoms independently selected from oxygen,nitrogen or sulfur, said heterocyclic ring system being substituted with0-3 R¹² ; R^(11A) is selected from one or more of the following:H, keto,halogen, cyano, --CH₂ N(R^(13A))R(^(14A)), --N(R^(13A))R(^(14A)), --CO₂H, --OC(═O)(C₁ -C₃ alkyl), --OH, C₂ -C₆ alkoxyalkyl, --C(═O)NH₂,--OC(═O)NH₂, --NHC(═O)NH₂, --SO₂ NH₂, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₃-C₁₀ cycloalkyl, C₃ -C₆ cycloalkylmethyl, benzyl, phenethyl, phenoxy,benzyloxy, nitro, C₇ -C₁₀ arylalkyl, hydroxamic acid, hydrazide, boronicacid, C₃ -C₆ cycloalkoxy, C₁ -C₄ alkyl substituted with --NH₂, C₁ -C₄hydroxyalkyl, methylenedioxy, ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄haloalkoxy, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄alkylcarbonyl, C₁ -C₄ alkylcarbonylamino, --OCH₂ CO₂ H,2-(1-morpholino)ethoxy, azido, aryl(C₁ -C₃ alkyl), a C₅ -C₁₄ carbocyclicresidue; a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system substituted with 0-3 R^(12A). R¹², when asubstituent on carbon, is selected from one or more of thefollowing:phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen,hydroxy, nitro, cyano, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆cycloalkylmethyl, C₇ -C₁₀ arylalkyl, C₁ -C₄ alkoxy, --CO₂ H, hydroxamicacid, hydrazide, boronic acid, sulfonamide, formyl, C₃ -C₆ cycloalkoxy,--OR¹³, C₁ -C₄ alkyl substituted with --NR¹³ R¹⁴, --NR¹³ R¹⁴, C₂ -C₆alkoxyalkylene optionally substituted with --Si(CH₃)₃, C₁ -C₄hydroxyalkyl, methylenedioxy, ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄haloalkoxy, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄alkylcarbonyl, C₁ -C₄ alkylcarbonylamino, --S(O)_(m) R¹³, --SO₂ NR¹³R¹⁴, --NHSO₂ R¹⁴, --OCH₂ CO₂ R¹³, 2-(1-morpholino)ethoxy,--C(R¹⁴)═N(OR¹⁴); or a 5- or 6-membered heterocyclic ring containingfrom 1 to 4 heteroatoms independently selected from oxygen, nitrogen orsulfur; or R¹² may be a 3- or 4-carbon chain attached to adjacentcarbons on the ring to form a fused 5- or 6-membered ring, said 5- or6-membered ring being optionally substituted on the aliphatic carbonswith halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, or --NR¹³ R¹⁴ ; or,when R¹² is attached to a saturated carbon atom, it may be ═O or ═S; orwhen R¹² is attached to sulfur it may be ═O; R¹², when a substituent onnitrogen, is selected from one or more of the following:phenyl, benzyl,phenethyl, hydroxy, C₁ -C₄ hydroxyalkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkyl, C₃-C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, C₂-C₆ alkoxyalkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxycarbonyl, --CO₂ H, C₁-C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl, --C(R¹⁴)═N(OR¹⁴); R^(12A),when a substituent on carbon, is selected from one or more of thefollowing:phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen,hydroxy, nitro, cyano, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆cycloalkylmethyl, C₇ -C₁₀ arylalkyl, C₁ -C₄ alkoxy, --CO₂ H, hydroxamicacid, hydrazide, boronic acid, sulfonamide, formyl, C₃ -C₆ cycloalkoxy,--OR¹³, C₁ -C₄ alkyl substituted with --NH₂, --NH₂, --NHMe, C₂ -C₆alkoxyalkyl optionally substituted with --Si(CH₃)₃, C₁ -C₄ hydroxyalkyl,methylenedioxy, ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, C₁-C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl, C₁-C₄ alkylcarbonylamino, --S(O)_(m) Me, --SO₂ NH₂, --NHSO₂ Me, --OCH₂ CO₂R¹³, 2-(1-morpholino)ethoxy, --C(═NOH)NH₂ ; or a 5- or 6-memberedheterocyclic ring containing from 1 to 4 heteroatoms independentlyselected from oxygen, nitrogen or sulfur; or R^(12A) may be a 3- or 4-carbon chain attached to adjacent carbons on the ring to form a fused 5-or 6-membered ring, said 5- or 6- membered ring being optionallysubstituted on the aliphatic carbons with halogen, C₁ -C₄ alkyl, C₁ -C₄alkoxy, hydroxy, or --NH₂ ; or, when R^(12A) is attached to a saturatedcarbon atom, it may be ═O or ═S; or when R¹² is attached to sulfur itmay be ═O; R^(12A), when a substituent on nitrogen, is selected from oneor more of the following:phenyl, benzyl, phenethyl, hydroxy, C₁ -C₄hydroxyalkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆cycloalkylmethyl, --CH₂ NH₂, --NH₂, C₂ -C₆ alkoxyalkyl, C₁ -C₄haloalkyl, C₁ -C₄ alkoxycarbonyl, --CO₂ H, C₁ -C₄ alkylcarbonyloxy, C₁-C₄ alkylcarbonyl, --C(═NOH)NH₂ ; R¹³ is selected from:H; phenylsubstituted with 0-3 R^(11A) ; benzyl substituted with 0-3 R^(11A) ; C₁-C₆ alkyl substituted with 0-3 R^(11A) ; C₂ -C₄ alkenyl substituted with0-3 R^(11A) ; C₁ -C₆ alkylcarbonyl substituted with 0-3 R^(11A) ; C₁ -C₆alkoxycarbonyl substituted with 0-3 R^(11A) ; C₁ -C₆ alkylaminocarbonylsubstituted with 0-3 R^(11A) ; and C₃ -C₆ alkoxyalkyl substituted with0-3 R^(11A) ; R¹⁴ is hydrogen, hydroxy, C₁ -C₆ alkyl substituted with0-3 groups selected from OH, C₁ -C₄ alkoxy, halogen, NH₂, --NH(C₁ -C₄alkyl), C₁ -C₆ alkoxy, C₂ -C₆ alkenyl, phenyl, and benzyl; R¹³ and R¹⁴can alternatively join to form --(CH₂)₄ --, --(CH₂)₅ --, --CH₂ CH₂N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --; R^(13A) and R^(14A) areindependently selected from: H, C₁ -C₆ alkyl; R^(13A) and R^(14A) canalternatively join to form --(CH₂)₄ --, --(CH₂)₅ --, --CH₂ CH₂ N(R¹⁵)CH₂CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --; R¹⁵ is H or CH₃ ; m is 0, 1 or 2; W isselected from:--N(R²²)C(═Z)N(R²³)--; --N(R²²)S(═Z')N(R²³)--;--N(R²²)S(═Z')₂ N(R²³)--; and --N(R²²)P(═O)(R^(24a))N(R²³)--;wherein: Zis O, S, NR²⁴ ; Z' is O or NR²⁴ ; R²² and R²³ are independently selectedfrom the following:hydrogen; --OR^(22a) ; --N(R^(22a))(R^(22b)); C₁ -C₈alkyl substituted with 0-3 R³¹ ; C₂ -C₈ alkenyl substituted with 0-3 R³¹; C₂ -C₈ alkynyl substituted with 0-3 R³¹ ; a C₃ -C₁₄ carbocyclic ringsystem substituted with 0-5 R³¹ or 0-5 R³² ; a heterocyclic ring systemselected independently from pyridinyl, pyrimidinyl, pyrazolyl,imidazolyl, tetrazoyl, triazinyl, pyrazinyl, pyridazinyl, oxazolidinyl,and thiazolyl, said heterocyclic ring system being substituted with 0-2R³² ; R^(22a) and R^(22b) are independently selected from thefollowing:hydrogen; C₁ -C₈ alkyl substituted with 0-3 R³¹ ; C₂ -C₈alkenyl substituted with 0-3 R³¹ ; C₂ -C₈ alkynyl substituted with 0-3R³¹ ; a C₃ -C₁₄ carbocyclic ring system substituted with 0-5 R³¹ or 0-5R³² ; a heterocyclic ring system selected independently from pyridinyl,furanyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, imidazolyl, indolyl,benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl,benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl, saidheterocyclic ring system being substituted with 0-2 R³² ; R²⁴ isselected from: hydrogen; hydroxy; amino; C₁ -C₄ alkyl; C₁ -C₄ alkoxy;mono- or di-(C₁ -C₆ alkyl)amino; cyano; nitro; benzyloxy; --NHSO₂ aryl,aryl being optionally substituted with (C₁ -C₆)alkyl; R^(24a) isselected from: hydroxy; amino; C₁ -C₄ alkyl; C₁ -C₄ alkoxy; mono- ordi-(C₁ -C₆ alkyl)amino; cyano; nitro; benzyloxy; or phenoxy;alternatively, R²² can join with R⁴ or R^(4A) to form a 5- or 6-memberedfused heterocyclic ring or carbocyclic ring substituted with 0-2 R¹²,said heterocyclic ring selected from pyrrolidine, morpholine,thiomorpholine, piperidine, or piperazine; or alternatively, R²³ canjoin with R⁷ or R^(7A) to form a 5- or 6-membered fused heterocyclicring or carbocyclic ring substituted with 0-2 R¹², said heterocyclicring selected from pyrrolidine, morpholine, thiomorpholine, piperidine,or piperazine; or alternatively, R²² or R²³, can join with R⁵ or R⁶ toform a 0- to 7-membered bridge to form a carbocyclic or heterocyclicring, said bridge being substituted with 0-2 R¹² and said heterocyclicring being selected from pyrrolidine, morpholine, thiomorpholine,piperidine, or piperazine; alternatively R²³ can join with R^(7A) toform a direct bond; alternatively R²² can join with R^(4A) to form adirect bond; R³¹ is selected from one or more of the following:keto,halogen, cyano, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, --CO₂ R¹³, --C(═O)R¹¹,--OC(═O)R¹³, --OR¹³, C₂ -C₆ alkoxyalkyl, --S(O)_(m) R¹³,--NHC(═NH)NHR¹³, --C(═NH)NHR¹³, --C(═O)NR¹³ R¹⁴, --NR¹⁴ C(═O)R¹³,═NOR¹⁴, --NR¹⁴ C(═O)OR¹⁴, --OC(═O)NR¹³ R¹⁴, --NR¹³ C(═O)NR¹³ R¹⁴, --NR¹³C(═S)NR¹³ R¹⁴, --NR¹⁴ SO₂ NR¹³ R¹⁴, --NR¹⁴ SO₂ R¹³, --SO₂ NR¹³ R¹⁴, C₁-C₄ alkyl, C₂ -C₄ alkenyl, C₃ -C₁₀ cycloalkyl, C₃ -C₆ cycloalkylmethyl,benzyl, phenethyl, phenoxy, benzyloxy, nitro, C₇ -C₁₀ arylalkyl,hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C₃-C₆ cycloalkoxy, C₁ -C₄ alkyl substituted with --NR¹³ R¹⁴, C₁ -C₄hydroxyalkyl, methylenedioxy, ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄haloalkoxy, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄alkylcarbonyl, C₁ -C₄ alkylcarbonylamino, --OCH₂ CO₂ R¹³,2-(1-morpholino)ethoxy, azido, --C(R¹⁴)═N(OR¹⁴); or - 3amino acids,linked together via amide bonds, said amino acid being linked via theamine or carboxylate terminus; a C₅ -C₁₄ carbocyclic residue substitutedwith 0-5 R³² ; or a 5- to 10-membered heterocyclic ring systemcontaining 1 to 4 heteroatoms independently selected from oxygen,nitrogen or sulfur, said heterocyclic ring system being substituted with0-2 R³² ; R³², when a substituent on carbon, is selected from one ormore of the following:phenethyl, phenoxy, C₃ -C₁₀ cycloalkyl, C₃ -C₆cycloalkylmethyl, C₇ -C₁₀ arylalkyl, hydrazide, oxime, boronic acid, C₂-C₆ alkoxyalkyl, methylenedioxy, ethylenedioxy, C₁ -C₄ alkylcarbonyloxy,--NHSO₂ R¹⁴, benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO₂ R¹³,hydroxamic acid, --CONR¹³ NR¹³ R¹⁴, cyano, sulfonamide, --CHO, C₃ -C₆cycloalkoxy, --NR¹³ R¹⁴, --C(R¹⁴)═N(OR¹⁴), --NO₂, --OR¹³, --NR⁴⁰ R⁴¹,--SO_(m) R¹³, --SO_(m) NR¹³ R¹⁴, --C(═O)NR¹³ R¹⁴, --OC(═O)NR¹³ R¹⁴,--C(═O)R¹¹, --OC(═O)R¹¹, --OCO₂ R¹³, phenyl, --C(═O)NR¹³ -(C₁ -C₄alkyl)--NR¹³ R¹⁴, --C(═O)NR⁴⁰ R⁴¹, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy,C₂ -C₄ haloalkenyl, C₁ -C₄ haloalkynyl, or --C(═O)NR¹³ C(R¹¹)₂ NR¹³ R¹⁴; --C(═O)NR¹³ C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)NR¹³ --(C₁ -C₄ alkyl)--NR¹³CO₂ R¹³ ; --C(═O)N(R¹³)--(C₁ -C₄ alkyl)--R¹¹ ; or --C(═O)C(R¹¹)₂ NR¹³R¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ;--C(═O)--(C₁ -C₄ alkyl)--NR¹³ CO₂ R¹³ ; or C₁ -C₄ alkoxy substitutedwith 0-4 groups selected from: R¹¹, C₃ -C₆ cycloalkyl, --CO₂ R¹³,--C(═O)NR¹³ R¹⁴, --NR¹³ R¹⁴ or OH; C₁ -C₄ alkyl substituted with 0-4groups selected from: R¹¹, ═NR¹⁴, ═NNR¹³ C(═O)NR¹³ R¹⁴, ═NNR¹³C(═O)OR¹³, or --NR¹³ R¹⁴ ; C₂ -C₄ alkenyl substituted with 0-4 R¹¹ ; C₂-C₄ alkynyl substituted with 0-4 R¹¹ ; a 5- or 6-membered heterocyclicring containing from 1 to 4 heteroatoms independently selected fromoxygen, nitrogen or sulfur, substituted with 0-2 R¹² ; or R³² may be a3- or 4-carbon chain attached to adjacent carbons on the ring to form afused 5- or 6-membered ring, said 5- or 6-membered ring being optionallysubstituted on the aliphatic carbons with halogen, C₁ -C₄ alkyl, C₁ -C₄alkoxy, hydroxy, or --NR¹³ R¹⁴ ; or, when R³² is attached to a saturatedcarbon, it may be ═O, ═S, ═NOH; or when R³² attached to sulfur it may be═O. R³², when a substituent on nitrogen, is selected from one or more ofthe following:phenyl, benzyl, phenethyl, hydroxy, C₁ -C₄ hydroxyalkyl,C₁ -C₄ alkoxy, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl,--CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, C₂ -C₆ alkoxyalkyl, C₁ -C₄ haloalkyl, C₁ -C₄alkoxycarbonyl, --CO₂ H, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl,--C(R¹⁴)═N(OR¹⁴); R⁴⁰ is selected from: H, C₁ -C₃ alkyl; R⁴¹ is selectedfrom:--C(═O)NR¹³ R¹⁴ ; --C(═O)NR¹³ NR¹³ R¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ;--C(═O)C(R¹¹)₂ NR¹³ NR¹³ R¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)H;--C(═O)R¹¹ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ; --C(═O)--(C₁ -C₄alkyl)--NR¹³ CO₂ R¹³ ; - 3amino acids linked together via amide bonds,and linked to the N atom via the carboxylate terminus;wherein said arylgroup is phenyl or naphthyl; provided that:R⁴, R^(4A), R⁷ and R^(7A) arenot all hydrogen; when R⁴, R^(4A) are hydrogen, then R²² is nothydrogen.
 2. A pharmaceutical composition of claim 1, wherein:R⁴ and R⁷are independently selected from the following groups:hydrogen; C₁ -C₈alkyl substituted with 0-3 R¹¹ ; C₂ -C₈ alkenyl substituted with 0-3 R¹¹; C₂ -C₈ alkynyl substituted with 0-3 R¹¹ ; C₃ -C₈ cycloalkylsubstituted with 0-3 R¹¹ ; C₆ -C₁₀ bicycloalkyl substituted with 0-3 R¹¹; aryl substituted with 0-3 R¹² ; a C₆ -C₁₄ partially unsaturatedcarbocyclic residue substituted with 0-3 R¹² ; a heterocyclic ringsystem selected independently from indolyl, furanyl, pyridyl, thienyl,pyrrolyl, pyrazolyl, thiazolyl, or imidazolyl, said heterocyclic ringsystem being substituted with 0-2 R¹² ; and R²² and R²³ areindependently selected from the following:hydrogen; C₁ -C₈ alkylsubstituted with 0-3 R³¹ ; C₂ -C₈ alkenyl substituted with 0-3 R³¹ ; C₂-C₈ alkynyl substituted with 0-3 R³¹ ; C₃ -C₈ cycloalkyl substitutedwith 0-3 R³¹ ; C₆ -C₁₀ bicycloalkyl substituted with 0-3 R³¹ ; arylsubstituted with 0-5 R³² ; a C₆ -C₁₄ partially unsaturated carbocyclicresidue substituted with 0-3 R³² ; a heterocyclic ring system selectedindependently from pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl,tetrazoyl, triazinyl, pyrazinyl, pyridazinyl, oxazolidinyl, andthiazolyl, said heterocyclic ring system being substituted with 0-2 R³².3. A pharmaceutical composition of claim 1, wherein:R⁴ and R⁷ areindependently selected from the following groups:hydrogen; C₁ -C₄ alkylsubstituted with 0-3 R¹¹ ; C₃ -C₄ alkenyl substituted with 0-3 R¹¹ ; C₃-C₄ alkynyl substituted with 0-3 R¹¹ ; R^(4A) and R^(7A) are hydrogen; nis 1; R⁵ is selected from fluoro, --OR²⁰, --N(R²⁰)₂ ; R⁶ isindependently selected from: hydrogen, fluoro or --OR²¹ ; R⁵ and R⁶ canalternatively join to form an epoxide or aziridine ring; --OCH₂ SCH₂O--; --OS(═O)O--; --OC(═O)O--; --OCH₂ O--; --OC(═S)O--;--OC(═O)C(═O)O--; --OC(CH₃)₂ O--; or --OC(OCH₃)(CH₂ CH₂ CH₃)O--; R^(5a)is selected from hydrogen or fluoro; R^(6a) is selected from: hydrogenor fluoro; R⁵ and R^(5a) can alternatively join to form ═O, ═S, or aketal ring; R⁶ and R^(6a) can alternatively join to form ═O, ═S, or aketal ring; R²⁰ and R²¹ are independently selected from:hydrogen; C₁ -C₆alkylcarbonyl; C₁ -C₆ alkoxycarbonyl; benzoyl; or phosphate ester R¹¹ isselected from one or more of the following:H, keto, halogen, cyano,--CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, --CO₂ R¹³, --OC(═O)R¹³, --OR¹³, C₂ -C₄alkoxyalkyl, --S(O)_(m) R¹³, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₃ -C₁₀cycloalkyl; a C₅ -C₁₄ saturated or partially unsaturated carbocyclicresidue substituted with 0-3 R¹² ; aryl(C₁ -C₃ alkyl)-, substituted with0-2 R¹² ; aryl substituted with 0-3 R¹² ; or a 5- to 10-memberedheterocyclic ring system containing 1 to 4 heteroatoms independentlyselected from oxygen, nitrogen or sulfur, said heterocyclic ring systembeing substituted with 0-2 R¹² ; R¹², when a substituent on carbon, isselected from one or more of the following:phenyl, benzyl, phenethyl,phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C₁ -C₄ alkyl, C₃ -C₆cycloalkyl, C₃ -C₆ cycloalkylmethyl, C₇ -C₁₀ arylalkyl, C₁ -C₄ alkoxy,2-(1-morpholino)ethoxy, --CO₂ H, hydroxamic acid, hydrazide,--C(R¹⁴)═N(OR¹⁴), cyano, boronic acid, sulfonamide, formyl, C₃ -C₆cycloalkoxy, --OR¹³, C₁ -C₄ alkyl substituted with --NR¹³ R¹⁴, --NR¹³R¹⁴, C₂ -C₆ alkoxyalkyl, C₁ -C₄ hydroxyalkyl, methylenedioxy,ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, C₁ -C₄alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl, C₁ -C₄alkylcarbonylamino, --S(O)_(m) R¹³, --SO₂ NR¹³ R¹⁴, --NHSO₂ R¹⁴ ; or a5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur; or R¹² may be a3- or 4-carbon chain attached to adjacent carbons on the ring to form afused 5- or 6-membered ring, said 5- or 6-membered ring being optionallysubstituted on the aliphatic carbons with halogen, C₁ -C₄ alkyl, C₁ -C₄alkoxy, hydroxy, or --NR¹³ R¹⁴ ; or, when R¹² is attached to a saturatedcarbon atom, it may be ═O or ═S; or when R¹² is attached to sulfur itmay be ═O; R¹², when a substituent on nitrogen, is selected from one ormore of the following:phenyl, benzyl, phenethyl, hydroxy, C₁ -C₄hydroxyalkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆cycloalkylmethyl, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, C₂ -C₆ alkoxyalkyl, C₁ -C₄haloalkyl, C₁ -C₄ alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄alkylcarbonyl, --CO₂ H; R¹³ is H, C₁ -C₆ alkyl, C₃ -C₆ alkoxyalkyl, C₂-C₄ alkenyl, phenyl, or benzyl; R¹⁴ is OH, H, CF₃, C₁ -C₄ alkyl, C₁ -C₄alkoxy, NH₂, C₂ -C₄ alkenyl, phenyl, or benzyl; R¹³ and R¹⁴ canalternatively join to form --(CH₂)₄ --, --(CH₂)₅ --, --CH₂ CH₂ N(R¹⁵)CH₂CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --; R¹⁵ is H or CH₃ ; m is 0, 1 or 2; W isselected from:--N(R²²)C(═Z)N(R²³)--; --N(R²²)S(═Z')N(R²³)--;--N(R²²)S(═Z')₂ N(R²³)--; --N(R²²)P(═O)(R^(24a))(N(R²³)--;wherein: Z isO, S, N--CN, N--OH, N--OCH₃ ; Z' is oxygen: R²² and R²³ areindependently selected from the following:hydrogen; C₁ -C₈ alkylsubstituted with 0-3 R³¹ ; C₃ -C₈ alkenyl substituted with 0-3 R³¹ ; C₃-C₈ alkynyl substituted with 0-3 R³¹ ; C₃ -C₆ cycloalkyl substitutedwith 0-3 R³¹ ; R^(24a) is selected from --OH, C₁ -C₄ alkoxy, mono- ordi-(C₁ -C₆ alkyl) amino; R³¹ is selected from one or more of thefollowing:keto, halogen, cyano, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, --CO₂ R¹³,--OC(═O)R¹³, --OR¹³, C₂ -C₄ alkoxyalkyl, --S(O)_(m) R¹³, C₁ -C₄ alkyl,C₂ -C₄ alkenyl, C₃ -C₁₀ cycloalkyl, benzyl, phenethyl, phenoxy,benzyloxy, nitro, C₇ -C₁₀ arylalkyl, hydroxamic acid, hydrazide, oxime,boronic acid, sulfonamide, formyl, C₃ -C₆ cycloalkoxy, C₁ -C₄ alkylsubstituted with --NR¹³ R¹⁴, C₁ -C₄ hydroxyalkyl, methylenedioxy,ethylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄ haloalkoxy, C₁ -C₄alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl, C₁ -C₄alkylcarbonylamino, --OCH₂ CO₂ H, 2-(1-morpholino)ethoxy,--C(R¹⁴)═N(OR¹⁴); or a C₅ -C₁₄ saturated or partially unsaturatedcarbocyclic residue substituted with 0-3 R³² ; aryl substituted with 0-3R³² ; or a 5- to 10-membered heterocyclic ring system containing 1 to 4heteroatoms independently selected from oxygen, nitrogen or sulfur, saidheterocyclic ring system being substituted with 0-2 R³² ; R³², when asubstituent on carbon, is selected from one or more of thefollowing:phenethyl, phenoxy, C₃ -C₆ cycloalkyl, C₃ -C₆cycloalkylmethyl, C₇ -C₁₀ arylalkyl, hydrazide, oxime, boronic acid, C₂-C₆ alkoxyalkyl, methylenedioxy, ethylenedioxy, C₁ -C₄ alkylcarbonyloxy,--NHSO₂ R¹⁴, benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO₂ R¹³,hydroxamic acid, --CONR¹³ NR¹³ R¹⁴, cyano, boronic acid, sulfonamide,--CHO, C₃ -C₆ cycloalkoxy, --NR¹³ R¹⁴, --C(R¹⁴)═N(OR¹⁴), NO₂, --OR¹³,--NR⁴⁰ R⁴¹, --SO_(m) R¹³, --SO_(m) NR¹³ R¹⁴, --C(═O)NR¹³ R¹⁴,--OC(═O)NR¹³ R¹⁴, --C(═O)R¹¹, --OC(═O)R¹¹, --OCO₂ R¹³, phenyl,--C(═O)NR¹³ --(C₁ -C₄ alkyl)--NR¹³ R¹⁴, --C(═O)NR⁴⁰ R⁴¹, C₁ -C₄haloalkyl, C₁ -C₄ haloalkoxy, C₂ -C₄ haloalkenyl, C₂ -C₄ haloalkynyl, or--C(═O)NR¹³ C(R¹¹)₂ NR¹³ R¹⁴ ; --C(═O)NR¹³ C(R¹¹)₂ NR¹³ NR¹⁴ ;--C(═O)NR¹³ C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)NR¹³ --(C₁ -C₄ alkyl)--NR¹³CO₂ R¹³ ; or --C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ NR¹⁴ ;--C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ;--C(═O)--(C₁ -C₄ alkyl)--NR¹³ CO₂ R¹³ ; or C₁ -C₄ alkoxy substitutedwith 0-3 groups selected from: R¹¹, C₃ -C₆ cycloalkyl, --CO₂ R¹³,--C(═O)NR¹³ R¹⁴, --NR¹³ R¹⁴ or OH; C₁ -C₄ alkyl substituted with 0-3groups selected from: R¹¹, ═NR¹⁴, ═NNR¹³ C(═O)NR¹³ R¹⁴ or --NR¹³ R¹⁴ ;C₂ -C₄ alkenyl substituted with 0-3 R¹¹ ; C₂ -C₄ alkynyl substitutedwith 0-3 R¹¹ ; a 5- or 6-membered heterocyclic ring containing from 1 to4 heteroatoms independently selected from oxygen, nitrogen or sulfur,substituted with 0-2 R¹² ; or R³² may be a 3- or 4-carbon chain attachedto adjacent carbons on the ring to form a fused 5- or 6-membered ring,said 5- or 6-membered ring being optionally substituted on the aliphaticcarbons with halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, hydroxy, or --NR¹³R¹⁴ ; or, when R³² is attached to a saturated carbon atom, it may be ═Oor ═S; or when R¹² is attached to sulfur it may be ═O; R³², when asubstituent on nitrogen, is selected from one or more of thefollowing:phenyl, benzyl, phenethyl, hydroxy, C₁ -C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, C₃ -C₆ cycloalkylmethyl,--CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, C₂ -C₆ alkoxyalkyl, C₁ -C₄ haloalkyl, C₁ -C₄alkoxycarbonyl, C₁ -C₄ alkylcarbonyloxy, C₁ -C₄ alkylcarbonyl, --CO₂ H,--C(R¹⁴)═N(OR¹⁴); R⁴⁰ is selected from: H, C₁ -C₃ alkyl; R⁴¹ is selectedfrom:--C(═O)NR¹³ R¹⁴ ; --C(═O)NR¹³ NR¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ;--C(═O)C(R¹¹)₂ NR¹³ NR¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)H;--C(═O)R¹¹ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ; --C(═O)--(C₁ -C₄alkyl)--NR¹³ CO₂ R¹³ ; - 3amino acids linked together via amide bonds,and linked to the N atom via the carboxylate terminus;wherein said arylgroup is phenyl or naphthyl; provided that:R⁴, R^(4A), R⁷, and R^(7A)are not all hydrogen; when R⁴ and R^(4A) are hydrogen, then R²² is nothydrogen.
 4. A pharmaceutical composition of claim 1 wherein thecompound is a compound of formula (II): ##STR113## or a pharmaceuticallyacceptable salt form thereof wherein: R⁴ and R⁷ are independentlyselected from the following groups:hydrogen; C₁ -C₄ alkyl substitutedwith 0-3 R¹¹ ; C₃ -C₄ alkenyl substituted with 0-3 R¹¹ ; R⁵ is --OR²⁰ ;R⁶ is hydrogen or --OR²¹ ; R²⁰ and R²¹ are hydrogen; R¹¹ is selectedfrom one or more of the following:H, keto, halogen, --CH₂ NR¹³ R¹⁴,--NR¹³ R¹⁴, --OR¹³, C₂ -C₄ alkoxyalkyl, C₂ -C₄ alkenyl; C₃ -C₁₀cycloalkyl substituted with 0-2 R¹² ; C₁ -C₄ alkyl substituted with 0-2R¹² ; aryl(C₁ -C₃ alkyl)-, substituted with 0-2 R¹² ; aryl substitutedwith 0-3 R¹² ; or a 5- to 10-membered heterocyclic ring systemcontaining 1 to 4 heteroatoms independently selected from oxygen,nitrogen or sulfur, said heterocyclic ring system being substituted with0-2 R¹² ; R¹², when a substituent on carbon, is selected from one ormore of the following:phenyl, benzyl, phenethyl, phenoxy, benzyloxy,halogen, C₁ -C₄ alkyl, C₇ -C₁₀ arylalkyl, C₁ -C₄ alkoxy,2-(1-morpholino)ethoxy, --CO₂ H, hydroxamic acid, hydrazide,--C(R¹⁴)═N(OR¹⁴), cyano, boronic acid, sulfonamide, formyl, C₃ -C₆cycloalkoxy, --OR¹³, C₁ -C₄ alkyl substituted with --NR¹³ R¹⁴, --NR¹³R¹⁴, methylenedioxy, C₁ -C₄ haloalkyl, C₁ -C₄ alkylcarbonyl, C₁ -C₄alkylcarbonylamino, hydroxy, hydroxymethyl; or a 5- or 6-memberedheterocyclic ring containing from 1 to 4 heteroatoms independentlyselected from oxygen, nitrogen or sulfur; R¹², when a substituent onnitrogen, is selected from benzyl or methyl; R¹³ is H, C₁ -C₄ alkyl, C₃-C₆ alkoxyalkyl, C₂ -C₄ alkenyl, or benzyl; R¹⁴ is OH, H, CF₃, C₁ -C₄alkyl, C₁ -C₄ alkoxy, NH₂, C₂ -C₄ alkenyl, or benzyl; R¹³ and R¹⁴ canalternatively join to form --(CH₂)₄ --, --(CH₂)₅ --, --CH₂ CH₂ N(R¹⁵)CH₂CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --; R¹⁵ is H or CH₃ ; W is selectedfrom:--N(R²²)C(═Z)N(R²³)--; --N(R²²)S(═Z')N(R²³)--; --N(R²²)S(═Z')₂N(R²³)--; --N(R²²)P(═O)(R^(24a))(N(R²³)--;wherein: z is O, S, or N--CN;Z' is O; R²² and R²³ are independently selected from thefollowing:hydrogen; C₁ -C₈ alkyl substituted with 0-2 R³¹ ; C₂ -C₆alkenyl substituted with 0-1 R³¹ ; C₂ -C₄ alkynyl substituted with 0-1R³¹ ; R^(24a) is selected from --OH, C₁ -C₄ alkoxy, mono- or di-(C₁ -C₆alkyl) amino; R³¹ is selected from one or more of the following:keto,halogen, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, --OR¹³, C₂ -C₄ alkoxyalkyl, C₁ -C₄alkyl, C₂ -C₄ alkenyl, C₃ -C₁₀ cycloalkyl, --C(R¹⁴)═N(OR¹⁴), --CO₂ R¹³,--S(O)_(m) R¹³ ; aryl substituted with 0-5 R³² ; or a 5- to 10-memberedheterocyclic ring system containing 1 to 4 heteroatoms independentlyselected from oxygen, nitrogen or sulfur, said heterocyclic ring systembeing substituted with 0-2 R³² ; R³², when a substituent on carbon, isselected from one or more of the following:phenethyl, phenoxy, C₃ -C₆cycloalkyl, C₃ -C₆ cycloalkylmethyl, C₇ -C₁₀ arylalkyl, hydrazide,oxime, boronic acid, C₂ -C₆ alkoxyalkyl, methylenedioxy, ethylenedioxy,C₁ -C₄ alkylcarbonyloxy, --NHSO₂ R¹⁴, benzyloxy, halogen,2-(1-morpholino)ethoxy, --CO₂ R¹³, hydroxamic acid, --CONR¹³ NR¹³ R¹⁴,cyano, boronic acid, sulfonamide, --CHO, C₃ -C₆ cycloalkoxy, --NR¹³ R¹⁴,--C(R¹⁴)═N(OR¹⁴), NO₂, --OR¹³, --NR⁴⁰ R⁴¹, --SO_(m) R¹³, --SO_(m) NR¹³R¹⁴, --C(═O)NR¹³ R¹⁴, --OC(═O)NR¹³ R¹⁴, --C(═O)R¹¹, --OC(═O)R¹¹, --OCO₂R¹³, phenyl, --C(═O)NR¹³ --(C₁ -C₄ alkyl)--NR¹³ R¹⁴, --C(═O)NR⁴⁰ R⁴¹, C₁-C₄ haloalkyl, C₁ -C₄ haloalkoxy, C₂ -C₄ haloalkenyl, C₂ -C₄haloalkynyl, or --C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ;--C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ CO₂R¹³ ; or C₁ -C₄ alkoxy substituted with 0-3 groups selected from: R¹¹,C₃ -C₆ cycloalkyl, --CO₂ R¹³, --C(═O)NR¹³ R¹⁴, --NR¹³ R¹⁴ or OH; C₁ -C₄alkyl substituted with 0-3 groups selected from: R¹¹, ═NR¹⁴, ═NNR¹³C(═O)NR¹³ R¹⁴ or --NR¹³ R¹⁴ ; C₂ -C₄ alkenyl substituted with 0-3 R¹¹ ;C₂ -C₄ alkynyl substituted with 0-3 R¹¹ ; a 5- or 6-memberedheterocyclic ring containing from 1 to 4 heteroatoms independentlyselected from oxygen, nitrogen or sulfur, substituted with 0-3 R¹² ;R³², when a substituent on nitrogen, is selected from benzyl or methyl;m is 0, 1, or 2; R⁴⁰ is selected from: H, C₁ -C₃ alkyl; R⁴¹ is selectedfrom:--C(═O)NR¹³ R¹⁴ ; --C(═O)NR¹³ NR¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ;--C(═O)C(R¹¹)₂ NR¹³ NR¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)H;--C(═O)R¹¹ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ; --C(═O)--(C₁ -C₄alkyl)--NR¹³ CO₂ R¹³ ; - 3amino acids linked together via amide bonds,and linked to the N atom via the carboxylate terminus;wherein said arylgroup is phenyl or naphthyl; provided that:R⁴ and R⁷ are not bothhydrogen; when R⁴ is hydrogen, then R²² is not hydrogen.
 5. Apharmaceutical composition of claim 4, wherein:R⁴ and R⁷ areindependently selected from the following groups:hydrogen; C₁ -C₃ alkylsubstituted with 0-1 R¹¹ ; R⁵ is --OR²⁰ ; R⁶ is hydrogen or --OR²¹ ; R²⁰and R²¹ are hydrogen; R¹¹ is selected from one or more of thefollowing:H; halogen; --OR¹³ ; C₃ -C₁₀ cycloalkyl substituted with 0-2R¹² ; C₁ -C₄ alkyl substituted with 0-2 R¹² ; aryl(C₁ -C₃ alkylene)substituted with 0-2 R¹² ; aryl substituted with 0-2 R¹² ; or aheterocyclic ring system selected from pyridyl, pyrimidinyl, triazinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, indolyl, quinolinyl, isoquinolinyl, oxazolidinyl, saidheterocyclic ring system being substituted with 0-2 R¹² ; R¹², when asubstituent on carbon, is selected from one or more of thefollowing:benzyloxy, halogen, methyl, C₁ -C₄ alkoxy, CF₃,2-(1-morpholino)ethoxy, --CO₂ H, hydroxamic acid, hydrazide,--C(R¹⁴)═N(OR¹⁴), cyano, boronic acid, sulfonamide, formyl, C₃ -C₆cycloalkoxy, C₁ -C₄ alkyl substituted with --NR¹³ R¹⁴, --NR¹³ R¹⁴,hydroxy, hydroxymethyl; or R¹², when a substituent on nitrogen, ismethyl; R¹³ is H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, or benzyl; R¹⁴ is OH, H,CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, NH₂, C₂ -C₄ alkenyl, or benzyl; R¹³and R¹⁴ can alternatively join to form --(CH₂)₄ --, --(CH₂)₅ --, --CH₂CH₂ N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --; R¹⁵ is H or CH₃ ; W isselected from:--N(R²²)C(═Z)N(R²³)--; --N(R²²)S(═Z')N(R²³)--;--N(R²²)S(═Z')₂ N(R²³)--; Z is O, S, or N--CN; Z' is O; R²² and R²³ areindependently selected from the following:hydrogen; C₁ -C₈ alkylsubstituted with 0-3 R³¹ ; C₂ -C₆ alkenyl substituted with 0-3 R³¹ ; C₂-C₄ alkynyl substituted with 0-3 R³¹ ; R³¹ is selected from one or moreof the following:halogen, --OR¹³, C₁ -C₄ alkyl, C₃ -C₁₀ cycloalkyl,--C(R¹⁴)═N(OR¹⁴), --CO₂ R¹³, --S(O)_(m) R¹³ ; aryl substituted with 0-5R³² ; or a heterocyclic ring system chosen from pyridyl, pyrimidinyl,triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl,oxazolidinyl, said heterocyclic ring being substituted with 0-2 R³² ;R³², when a substituent on carbon, is selected from one or more of thefollowing:benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO₂ R¹³,hydroxamic acid, --CONR¹³ NR¹³ R¹⁴, cyano, boronic acid, sulfonamide,--CHO, C₃ -C₆ cycloalkoxy, --NR¹³ R¹⁴, --C(R¹⁴)═N(OR¹⁴), NO₂, --OR¹³,--NR⁴⁰ R⁴¹, --SO_(m) R¹³, --SO_(m) NR¹³ R¹⁴, --C(═O)NR¹³ R¹⁴,--OC(═O)NR¹³ R¹⁴, --C(═O)R¹¹, --OC(═O)R¹¹, --OCO₂ R¹³, phenyl,--C(═O)NR¹³ --(C₁ -C₄ alkyl)--NR¹³ R¹⁴, --C(═O)NR⁴⁰ R⁴¹, C₁ -C₄haloalkyl, C₁ -C₄ haloalkoxy, C₂ -C₄ haloalkenyl, C₂ -C₄ haloalkynyl,--C(═O)NR¹³ R¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ NR¹⁴ ;--C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ;--C(═O)--(C₁ -C₄ alkyl)--NR¹³ CO₂ R¹³ ; or C₁ -C₄ alkoxy substitutedwith 0-3 groups selected from: R¹¹, C₃ -C₆ cycloalkyl, --C(═O)NR¹³ R¹⁴,--NR¹³ R¹⁴ or OH; C₁ -C₄ alkyl substituted with 0-3 groups selectedfrom: R¹¹, ═NR¹⁴, ═NNR¹³ C(═O)NR¹³ R¹⁴ or --NR¹³ R¹⁴ ; C₂ -C₄ alkenylsubstituted with 0-3 R¹¹ ; C₂ -C₄ alkynyl substituted with 0-3 R¹¹ ; a5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur, substituted with0-2 R¹² ; R³², when a substituent on nitrogen, is methyl; m is 0, 1, or2; R⁴⁰ is selected from: H, C₁ -C₃ alkyl; R⁴¹ is selectedfrom:--C(═O)NR¹³ R¹⁴ ; --C(═O)NR¹³ NR¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ;--C(═O)C(R¹¹)₂ NR¹³ NR¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)H;--C(═O)R¹¹ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ; --C(═O)--(C₁ -C₄alkyl)--NR¹³ CO₂ R¹³ ; - 3amino acids linked together via amide bonds,and linked to the N atom via the carboxylate terminus;wherein said arylgroup is phenyl or naphthyl; provided that:R⁴ and R⁷ are not bothhydrogen; when R⁴ is hydrogen, then R²² is not hydrogen.
 6. Apharmaceutical composition of claim 1, wherein:R⁴ and R⁷ are selectedfrom benzyl, fluorobenzyl, methylbenzyl, dimethylbenzyl, ethylbenzyl,pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl, aminobenzyl,thienylmethyl, hydroxybenzyl, pyridylmethyl, or naphthylmethyl; R⁵ is--OH; R⁶ is hydrogen or --OH; R¹³ is H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, orbenzyl; R¹⁴ is OH, H, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, NH₂, C₂ -C₄alkenyl, or benzyl; R¹³ and R¹⁴ can alternatively join to form--(CH₂)4--, --(CH₂)₅ --, --CH₂ CH₂ N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂CH₂ --; W is selected from:--N(R²²)C(═O)N(R²³)--;--N(R²²)C(═N--CN)N(R²³)--; --N(R²²)S(═O)₂ N(R²³)--; or--N(R²²)C(═S)N(R²³)--; R²² and R²³ are independently selected from thefollowing:hydrogen; C₁ -C₈ alkyl substituted with 0-2 R³¹ ; C₂ -C₆alkenyl substituted with 0-2 R³¹ ; C₂ -C₄ alkynyl substituted with 0-2R³¹ ; R³¹ is selected from one or more of the following:halogen, --OR¹³,C₁ -C₄ alkyl, C₃ -C₁₀ cycloalkyl, --C(R¹⁴)═N(OR¹⁴), --CO₂ R¹³,--S(O)_(m) R¹³ ; aryl substituted with 0-5 R³² ; or a heterocyclic ringsystem chosen from pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, indolyl,quinolinyl, isoquinolinyl, oxazolidinyl, benzimidazolyl, benzotriazolyl,indazolyl, benzoxazolinyl, benzoxazolyl, said heterocyclic ring beingsubstituted with 0-2 R³² ; R³², when a substituent on carbon, isselected from one or more of the following:--CONH₂, --CO₂ H, --CHO,--CH₂ NHOH, --CH₂ NR¹³ R¹⁴, --NR¹³ R¹⁴, hydroxy, hydroxymethyl,--C(R¹⁴)═N(OR¹⁴), halogen, methoxy, methyl, nitro, cyano, allyloxy,--CO₂ CH₃, --NHCHO, --NHCOCH₃, --OCO₂ CH₃, --CH═NCH₂ CH₂ OH, --OCONHCH₂C₆ H₅, --OCONHCH₃, oxazolidinyl, --C.tbd.C--CH₂ OH, --COCH₃,hydroxyethyl, C₁ -C₃ alkyl (said alkyl substituted with 0-4 halogen, orOH), tetrazolyl, --OCH₂ CONH₂, --CONHNH₂, --CH═NNHCONH₂, --CONHOCH₃,--CH₂ CH(OH)CH₂ OH, adamantamido, hydroxyethoxy, dihydroxyethyl,--C(NH₂)═NH, --CONHCH₃, --B(OH)₂, benzyloxy, --CONHCH₂ CH₃, --CON(CH₂CH₃)₂, methylthio, --SO₂ CH₃, --NHCONH₂, --NHCONHCH₃, --NHCOCH₂ N(CH₃)₂,--NHCOCH₂ NHCH₃, --NHCOCH₂ NHCO₂ CH₂ C₆ H₅, --NHCOCH₂ NH₂,--NHCOCH(CH₃)NHCO₂ CH₂ C₆ H₅, --NHCOCH(CH₂ C₆ H₅)NHCO₂ CH₂ C₆ H₅,--NHCOCH(CH₃)NH₂, --NHCOCH(CH₂ C₆ H₅)NH₂, --CO₂ CH₂ CH₃, --CONHCH₂ CH₂CH₃, --CONHCH(CH₃)₂, --CH₂ -imidazole, --COC(CH₃)₃, --CH(OH)CF₃,--CO-imidazole, --CO-pyrazolyl, --CO--CH₂ -pyridine, oxadiazolyl,--COCF₃, --COCH₂ CH₃, --COCH₂ CH₂ CH₃, imidazolyl, pyrazolyl, --SO₂ NH₂,--C(CH₂ CH₃)═N(OH) or --C(CF₃)═N(OH), phenyl, acetoxy, hydroxyamino,--N(CH₃)(CHO), cyclopropylmethoxy, --CONR¹³ R¹⁴, --CONHOH,(diethylaminoethyl)aminocarbonyl,(N-ethyl,N-methylaminoethyl)aminocarbonyl,(4-methylpiperazinylethyl)aminocarbonyl,(pyrrolidinylethyl)aminocarbonyl, (piperidinylethyl)aminocarbonyl,--NHCOCH₂ NHCH₃, N-(2-(4-morpholino)ethyl)aminocarbonyl,N-(2-(N,N-dimethylamino)ethyl)aminocarbonyl; wherein said oxazolidinyl,tetrazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyrrolidinyl, andpiperidinyl groups are optionally substituted with 1-2 groupsindependently selected from OH, --O(C₁ -C₃ alkyl), NH₂, --NH(C₁ -C₃alkyl), or halogen; R³², when a substituent on nitrogen, is methyl.
 7. Apharmaceutical composition of claim 1, wherein the compound is acompound of formula: ##STR114## or a pharmaceutically acceptable saltform thereof, wherein: Z is O, S, or N--CN;R⁴ and R⁷ are independentlyselected from: benzyl, methylbenzyl, dimethylbenzyl, ethylbenzyl,fluorobenzyl, pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl,aminobenzyl, thienylmethyl, hydroxybenzyl, pyridylmethyl, ornaphthylmethyl; R²² and R²³ are independently selected from the groupconsisting of:hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl,n-butyl, i-butyl, CH₂ CH═C(CH₃)₂, pyridinylmethyl, methallyl, n-pentyl,i-pentyl, hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl,cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyl-oxazolinylmethyl,naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl,pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl,benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl,methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl,hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl,allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl,chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl,cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl,(H₂ NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl,tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl,(O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH₃ O₂CO)-benzyl, (HOCH₂ CH₂ N═CH)-benzyl, N-benzylaminocarbonylbenzyl,N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl,acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethyl-boronicacid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH₃C(═NOH))-benzyl, (H₂ NNHC(═O))-benzyl, (H₂ NC(═O)NHN═CH)-benzyl, (CH₃₀NHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH₃ NHC(═O))-benzyl,N,N-dimethylaminocarbonylbenzyl, (HOCH₂ CH(OH)CH₂ O)-benzyl,hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl,(hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl,(methylthio)benzyl, (methylsulfonyl)benzyl,N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl,glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl,(N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl,(N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH₃ CH₂NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl,N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl,N,N-diisopropylaminocarbonylbenzyl, N, N-di-n-propylaminocarbonylbenzyl,(hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H₂NSO₂)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H₂NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl,methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl,propionylbenzyl, butyrylbenzyl, (CH₃ CH₂ C(═NOH))-benzyl,(trifluorohydroxyethyl)benzyl, (CF₃ C(═NOH))-benzyl,(N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl,(benzyl-NHC(═O)O)benzyl, (CH₃ NHC(═O)O)benzyl, (NH₂ C(═O)CH₂ O)benzyl,(NH₂ C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl,(imidazolylmethyl)benzyl, ((CH₃)₃ C--C(═O))benzyl,(N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl,(pyrrolidinylethyl)aminocarbonylbenzyl,(piperidinylethyl)aminocarbonylbenzyl, (H₂ NC(═NOH))benzyl, (H₂NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl,indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl,thienylmethyl, furylmethyl.
 8. A pharmaceutical composition of claim 1,wherein the compound is a compound of formula (IIa): ##STR115## or apharmaceutically acceptable salt form thereof, wherein: wherein R²² andR²³ are independently selected from the group consisting of:hydrogen,allyl, methyl, ethyl, propyl, cyclopropylmethyl, n-butyl, i-butyl, CH₂CH═C(CH₃)₂, pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl,benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl,dimethyl-butyl, ethoxyethyl, methyl-oxazolinylmethyl, naphthylmethyl,methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl,quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl,phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl,methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl,aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl,fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl,fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl,formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H₂ NC(═O))-benzyl,carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, anddimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl,(O-methyl-formaldoxime)benzyl, (CH₃ O₂ CO)-benzyl, (HOCH₂ CH₂N═CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl,N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl,acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethyl-boronic acid,N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH₃C(═NOH))-benzyl, (H₂ NNHC(═O))-benzyl, (H₂ NC(═O)NHN═CH)-benzyl, (CH₃₀NHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH₃ NHC(═O))-benzyl,N,N-dimethylaminocarbonylbenzyl, (HOCH₂ CH(OH)CH₂ O)-benzyl,hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl,(hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl,(methylthio)benzyl, (methylsulfonyl)benzyl,N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl,glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl,(N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl,(N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH₃ CH₂NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl,N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl,N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl,(hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H₂NSO₂)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H₂NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl,methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl,propionylbenzyl, butyrylbenzyl, (CH₃ CH₂ C(═NOH))-benzyl,(trifluorohydroxyethyl)benzyl, (CF₃ C(═NOH))-benzyl,(N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl,(benzyl-NHC(═O)O)benzyl, (CH₃ NHC(═O)O)benzyl, (NH₂ C(═O)CH₂ O)benzyl,(NH₂ C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl,(imidazolylmethyl)benzyl, ((CH₃)₃ C--C(═O))benzyl,(N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl,(pyrrolidinylethyl)aminocarbonylbenzyl,(piperidinylethyl)aminocarbonylbenzyl, (H₂ NC(═NOH))benzyl, (H₂NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl,indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl,thienylmethyl, furylmethyl.
 9. A pharmaceutical composition of claim 1,wherein the compound is a compound of formula (IIa): ##STR116## or apharmaceutically acceptable salt form thereof, selected from the groupconsisting of:the compound of formula (IIa) wherein R²² is allyl and R²³is allyl; the compound of formula (IIa) wherein R²² is propyl and R²³ ispropyl; the compound of formula (IIa) wherein R²² is cyclopropylmethyland R²³ is cyclopropylmethyl; the compound of formula (IIa) wherein R²²is n-hexyl and R²³ is n-hexyl; the compound of formula (IIa) wherein R²²is n-butyl and R²³ is n-butyl; the compound of formula (IIa) wherein R²²is CH₂ CH═C(CH₃)₂ and R²³ is CH₂ CH═C(CH₃)₂ ; the compound of formula(IIa) wherein R²² is CH₂ CH═C(CH₃)₂ and R²³ is H; the compound offormula (IIa) wherein R²² is i-pentyl and R²³ is i-pentyl; the compoundof formula (IIa) wherein R²² is 2-methallyl and R²³ is 2-methallyl; thecompound of formula (IIa) wherein R²² is n-pentyl and R²³ is n-pentyl;the compound of formula (IIa) wherein R²² is benzyl and R²³ is benzyl;the compound of formula (IIa) wherein R²² is i-hexyl and R²³ is i-hexyl;the compound of formula (IIa) wherein R²² is allyl and R²³ is isoprenyl;the compound of formula (IIa) wherein R²² is 1-cinnamyl and R²³ is1-cinnamyl; the compound of formula (IIa) wherein R²² is 4-fluorobenzyland R²³ is 4-fluorobenzyl; the compound of formula (IIa) wherein R²² iscyclopropylmethyl and R²³ is benzyl; the compound of formula (IIa)wherein R²² is allyl and R²³ is benzyl; the compound of formula (IIa)wherein R²² is CH₂ CH═C(CH₃)₂ and R²³ is cyclopropylmethyl; the compoundof formula (IIa) wherein R²² is 2-naphthylmethyl and R²³ is2-napthylmethyl; the compound of formula (IIa) wherein R²² is n-butyland R²³ is benzyl; the compound of formula (IIa) wherein R²² is allyland R²³ is cyclopropylmethyl; the compound of formula (IIa) wherein R²²is n-butyl and R²³ is cyclopropylmethyl; the compound of formula (IIa)wherein R²² is CH₂ CH═C(CH₃)₂ and R²³ is benzyl; the compound of formula(IIa) wherein R²² is benzyl and R²³ is ethyl; the compound of formula(IIa) wherein R²² is benzyl and R²³ is 4-pyridinylmethyl; the compoundof formula (IIa) wherein R²² is cyclopropylmethyl and R²³ is4-pyridinylmethyl; the compound of formula (IIa) wherein R²² is benzyland R²³ is cyclopentylmethyl; the compound of formula (IIa) wherein R²²is cyclopropylmethyl and R²³ is cyclopentylmethyl; the compound offormula (IIa) wherein R²² is benzyl and R²³ is n-propyl; the compound offormula (IIa) wherein R²² is cyclopropylmethyl and R²³ is cinnamyl; thecompound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³ is2-naphthylmethyl; the compound of formula (IIa) wherein R²² iscyclopentylmethyl and R²³ is 2-naphthylmethyl; the compound of formula(IIa) wherein R²² is benzyl and R²³ is 2-naphthylmethyl; the compound offormula (IIa) wherein R²² is cyclopropylmethyl and R²³ is2-pyridinylmethyl; the compound of formula (IIa) wherein R²² is3-cyanobenzyl and R²³ is 3-cyanobenzyl; the compound of formula (IIa)wherein R²² is allyl and R²³ is 2-naphthylmethyl; the compound offormula (IIa) wherein R²² is n-propyl and R²³ is 2-naphthylmethyl; thecompound of formula (IIa) wherein R²² is n-butyl and R²³ is2-naphthylmethyl; the compound of formula (IIa) wherein R²² is hydrogenand R²³ is 2-naphthylmethyl; the compound of formula (IIa) wherein R²²is 4-pyridinylmethyl and R²³ is 2-naphthylmethyl; the compound offormula (IIa) wherein R²² is allyl and R²³ is cyclopentylmethyl; thecompound of formula (IIa) wherein R²² is allyl and R²³ is2-quinolinylmethyl; the compound of formula (IIa) wherein R²² is3-pyridinylmethyl and R²³ is cyclopropylmethyl; the compound of formula(IIa) wherein R²² is 3-pyridinylmethyl and R²³ is 2-naphthylmethyl; thecompound of formula (IIa) wherein R²² is 3-hydroxybenzyl and R²³ is3-hydroxybenzyl; the compound of formula (IIa) wherein R²² isvinylbenzyl and R²³ is vinylbenzyl; the compound of formula (IIa)wherein R²² is 3-allyloxybenzyl and R²³ is 3-hydroxybenzyl; the compoundof formula (IIa) wherein R²² is 3-pyridinylmethyl and R²³ is3-pyridinylmethyl; the compound of formula (IIa) wherein R²² is2-naphthylmethyl and R²³ is 4-fluorobenzyl; the compound of formula(IIa) wherein R²² is 4-hydroxybenzyl and R²³ is 4-hydroxybenzyl; thecompound of formula (IIa) wherein R²² is 3-hydroxymethylbenzyl and R²³is 3-hydroxymethylbenzyl; the compound of formula (IIa) wherein R²² is3-carbomethoxybenzyl and R²³ is 3-carbomethoxybenzyl; the compound offormula (IIa) wherein R²² is 4-hydroxymethylbenzyl and R²³ is4-hydroxymethylbenzyl; the compound of formula (IIa) wherein R²² is3-formylbenzyl and R²³ is 3-formylbenzyl; the compound of formula (IIa)wherein R²² is 4-cyanobenzyl and R²³ is 4-cyanobenzyl; the compound offormula (IIa) wherein R²² is 4-formylbenzyl and R²³ is 4-formylbenzyl;the compound of formula (IIa) wherein R²² is 4-hydroxybenzyl and R²³ is2-propyl; the compound of formula (IIa) wherein R²² is 3-hydroxybenzyland R²³ is 2-propyl; the compound of formula (IIa) wherein R²² is3-carboxybenzyl and R²³ is 3-carboxybenzyl; the compound of formula(IIa) wherein R²² is 3-formaldoximebenzyl and R²³ is3-formaldoximebenzyl; the compound of formula (IIa) wherein R²² iscyclopropylmethyl and R²³ is 3-hydroxybenzyl; the compound of formula(IIa) wherein R²² is cyclopropylmethyl and R²³ is 4-hydroxybenzyl; thecompound of formula (IIa) wherein R²² is cyclobutylmethyl and R²³ iscyclobutylmethyl; the compound of formula (IIa) wherein R²² iscyclopentylmethyl and R²³ is cyclopentylmethyl; the compound of formula(IIa) wherein R²² is 3n-butyl and R²³ is CH₂ CH═C(CH₃)₂ ; the compoundof formula (IIa) wherein R²² is n-butyl and R²³ is cyclopentylmethyl;the compound of formula (IIa) wherein R²² is benzyl and R²³ is H; thecompound of formula (IIa) wherein R²² is 3-fluorobenzyl and R²³ is3-fluorobenzyl; the compound of formula (IIa) wherein R²² is3-methoxybenzyl and R²³ is 3-methoxybenzyl; the compound of formula(IIa) wherein R²² is 3,4-difluorobenzyl and R²³ is 3,4-difluorobenzyl;the compound of formula (IIa) wherein R²² is 4-methylbenzyl and R²³ is4-methylbenzyl; the compound of formula (IIa) wherein R²² is4-chlorobenzyl and R²³ is 4-chlorobenzyl; the compound of formula (IIa)wherein R²² is cyclopropylmethyl and R²³ is 4-fluorobenzyl; the compoundof formula (IIa) wherein R²² is 3-chlorobenzyl and R²³ is3-chlorobenzyl; the compound of formula (IIa) wherein R²² is3-nitrobenzyl and R²³ is 3-nitrobenzyl; the compound of formula (IIa)wherein R²² is 3-methylbenzyl and R²³ is 3-methylbenzyl; the compound offormula (IIa) wherein R²² is 3-bromobenzyl and R²³ is 3-bromobenzyl; thecompound of formula (IIa) wherein R²² is 4-fluorobenzyl and R²³ is H;the compound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³is 3-chlorobenzyl; the compound of formula (IIa) wherein R²² is3-aminobenzyl and R²³ is 3-aminobenzyl; the compound of formula (IIa)wherein R²² is 4-aminobenzyl and R²³ is 4-aminobenzyl; the compound offormula (IIa) wherein R²² is 3-nitrobenzyl and R²³ is H; the compound offormula (IIa) wherein R²² is 3-(NHCHO)benzyl and R²³ is 3-(NHCHO)benzyl;the compound of formula (IIa) wherein R²² is 3-(NHCOCH₃)benzyl and R²³is 3-(NHCOCH₃)benzyl; the compound of formula (IIa) wherein R²² is3,4-dihydroxybenzyl and R²³ is 3,4-dihydroxybenzyl; the compound offormula (IIa) wherein R²² is 3-formaldoximebenzyl and R²³ is3-(N-hydroxy)aminomethylbenzyl; the compound of formula (IIa) whereinR²² is 3-(N-hydroxy)aminomethylbenzyl and R²³ is3-(N-hydroxy)aminomethylbenzyl; the compound of formula (IIa) whereinR²² is 3-(CH₃ OC(═O)O--)benzyl and R²³ is 3-(CH₃ OC(═O)O--)benzyl; thecompound of formula (IIa) wherein R²² is 3-(1-hydroxyethyl)benzyl andR²³ is 3-(1-hydroxyethyl)benzyl; the compound of formula (IIa) whereinR²² is 3-(HOCH₂ CH₂ N═CH)benzyl and R²³ is 3-(HOCH₂ CH₂ N═CH)benzyl; thecompound of formula (IIa) wherein R²² is 3-(HOCH₂ CH₂ N═CH)benzyl andR²³ is 3-(2-oxazolidinyl)benzyl; the compound of formula (IIa) whereinR²² is 3-(C₆ H₅ CH₂ NHC(═O)O)benzyl and R²³ is 3-(C₆ H₅ CH₂NHC(═O)O)benzyl; the compound of formula (IIa) wherein R²² is 3-(CH₃NHC(═O)O)benzyl and R²³ is 3-(CH₃ NHC(═O)O)benzyl; the compound offormula (IIa) wherein R²² is 3-(HOCH₂ CC)benzyl and R²³ is3-bromobenzyl; the compound of formula (IIa) wherein R²² is3-acetylbenzyl and R²³ is 3-bromobenzyl; the compound of formula (IIa)wherein R²² is 3-acetylbenzyl and R²³ is 3-acetylbenzyl; the compound offormula (IIa) wherein R²² is 3-(CH₃ C(═NOH))benzyl and R²³ is 3-(CH₃C(═NOH))benzyl; the compound of formula (IIa) wherein R²² is3-(1-hydroxyethyl)benzyl and R²³ is 3-bromobenzyl; the compound offormula (IIa) wherein R²² is 3-(chloromethyl)benzyl and R²³ is3-(chloromethyl)benzyl; the compound of formula (IIa) wherein R²² is3-(5-tetrazolyl)benzyl and R²³ is cyclopropylmethyl; the compound offormula (IIa) wherein R²² is 3-cyanobenzyl and R²³ is 3-formylbenzyl;the compound of formula (IIa) wherein R²² is 4-acetoxybenzyl and R²³ is4-hydroxybenzyl; the compound of formula (IIa) wherein R²² is3-aminocarbonylbenzyl and R²³ is 3-aminocarbonylbenzyl; the compound offormula (IIa) wherein R²² is 3-(H₂ NCOCH₂ O)benzyl and R²³ is 3-(H₂NCOCH₂ O)benzyl; the compound of formula (IIa) wherein R²² is3-hydroxybenzyl and R²³ is H; the compound of formula (IIa) wherein R²²is 3-methylbenzyl and R²³ is 3-hydroxybenzyl; the compound of formula(IIa) wherein R²² is 2-naphthylmethyl and R²³ is 3-hydroxybenzyl; thecompound of formula (IIa) wherein R²² is 3-(H₂ NNHC(═O))-benzyl and R²³is 3-(H₂ NNHC(═O))-benzyl; the compound of formula (IIa) wherein R²² is4-(H₂ NNHC(═O))-benzyl and R²³ is 4-(H₂ NNHC(═O))-benzyl; the compoundof formula (IIa) wherein R²² is 4-hydroxymethylbenzyl and R²³ is3-hydroxybenzyl; the compound of formula (IIa) wherein R²² is 3-(H₂NC(═O)NHN═CH)-benzyl and R²³ is 3-(H₂ NC(═O)NHN═CH)-benzyl; the compoundof formula (IIa) wherein R²² is 3- (N-methoxy)aminocarbonyl!-benzyl andR²³ is 3- (N-methoxy)aminocarbonyl!-benzyl; the compound of formula(IIa) wherein R²² is 4- (N-methoxy)aminocarbonyl!-benzyl and R²³ is 4-(N-methoxy)aminocarbonyl!-benzyl; the compound of formula (IIa) whereinR²² is 3-(HOCH₂ CH(OH)CH₂ O)benzyl and R²³ is 3-(HOCH₂ CH(OH)CH₂O)benzyl; the compound of formula (IIa) wherein R²² is3-(2-hydroxyethoxy)benzyl and R²³ is 3-(2-hydroxyethoxy)benzyl; thecompound of formula (IIa) wherein R²² is 3-(1,2-dihydroxyethyl)benzyland R²³ is 4-(1,2-dihydroxyethyl)benzyl; the compound of formula (IIa)wherein R²² is 3-aminocarbonylbenzyl and R²³ is 3-(H₂ NC(═NH))benzyl;the compound of formula (IIa) wherein R²² is 4-hydroxybenzyl and R²³ is3-formyl-4-hydroxybenzyl; the compound of formula (IIa) wherein R²² is3-carbomethoxybenzyl and R²³ is 3-(N-methylaminocarbonyl)benzyl; thecompound of formula (IIa) wherein R²² is 3-(N-methylaminocarbonyl)benzyland R²³ is 3-(N-methylaminocarbonyl)benzyl; the compound of formula(IIa) wherein R²² is benzyl and R²³ is 3-hydroxybenzyl; the compound offormula (IIa) wherein R²² is 2-naphthylmethyl and R²³ is4-hydroxymethylbenzyl; the compound of formula (IIa) wherein R²² is3-(1,2-dihydroxyethyl)benzyl and R²³ is 3-(1,2-dihydroxyethyl)benzyl;the compound of formula (IIa) wherein R²² is4-(1,2-dihydroxyethyl)benzyl and R²³ is 4-(1,2-dihydroxyethyl)benzyl;the compound of formula (IIa) wherein R²² is 3-hydroxymethylbenzyl andR²³ is 3-(N-methylaminocarbonyl)benzyl; the compound of formula (IIa)wherein R²² is 4-hydroxymethylbenzyl and R²³ is hydrogen; the compoundof formula (IIa) wherein R²² is 3-(boronic acid)benzyl and R²³ is3-(boronic acid)benzyl; the compound of formula (IIa) wherein R²² is3-nitrobenzyl and R²³ is 3-benzyloxybenzyl; the compound of formula(IIa) wherein R²² is 3-aminobenzyl and R²³ is 3-hydroxybenzyl; thecompound of formula (IIa) wherein R²² is 3-(N-ethylaminocarbonyl)benzyland R²³ is 3-(N-ethylaminocarbonyl)benzyl; the compound of formula (IIa)wherein R²² is 3-carbomethoxybenzyl and R²³ is3-(N,N-diethylaminocarbonyl)benzyl; the compound of formula (IIa)wherein R²² is 3-carbomethoxybenzyl and R²³ is3-(N-ethylaminocarbonyl)benzyl; the compound of formula (IIa) whereinR²² is 6-hydroxy-1-hexyl and R²³ is hydrogen; the compound of formula(IIa) wherein R²² is 6-hydroxy-1-hexyl and R²³ is 6-hydroxy-1-hexyl; thecompound of formula (IIa) wherein R²² is cyclopropylmethyl and R²³ is6-hydroxy-1-hexyl; the compound of formula (IIa) wherein R²² is5-carboxy-1-pentyl and R²³ is 5-carboxy-1-pentyl; the compound offormula (IIa) wherein R²² is 3-iodobenzyl and R²³ is 3-iodobenzyl; thecompound of formula (IIa) wherein R²² is benzyl and R²³ is2-(hydroxymethyl)-cyclopropylmethyl; the compound of formula (IIa)wherein R²² is 3-(thiomethyl)benzyl and R²³ is 3-(thiomethyl)benzyl; thecompound of formula (IIa) wherein R²² is 3-(methylsulfonyl)benzyl andR²³ is 3-(methylsulfonyl)benzyl; the compound of formula (IIa) whereinR²² is 6-hexenyl and R²³ is 6-hexenyl; the compound of formula (IIa)wherein R²² is 6-bromo-5-hydroxy-1-hexyl and R²³ is6-bromo-5-hydroxy-1-hexyl; the compound of formula (IIa) wherein R²² is5-hydroxy-1-pentyl and R²³ is 5-hydroxy-1-pentyl; the compound offormula (IIa) wherein R²² is 3-aminobenzyl and R²³ is4-hydroxymethylbenzyl; the compound of formula (IIa) wherein R²² is3-(H₂ NC(═O)NH)benzyl and R²³ is 3-(H₂ NC(═O)NH)benzyl; the compound offormula (IIa) wherein R²² is 3-(N-methylamino)benzyl and R²³ is3-(N-methylamino)benzyl; the compound of formula (IIa) wherein R²² iscyclopropylmethyl and R²³ is 3-aminobenzyl; the compound of formula(IIa) wherein R²² is cyclopropylmethyl and R²³ is 3-nitrobenzyl; thecompound of formula (IIa) wherein R²² is 3-(N,N-dimethylamino)benzyl andR²³ is 3-(N,N-dimethylamino)benzyl; the compound of formula (IIa)wherein R²² is 3-nitrobenzyl and R²³ is 4-hydroxymethylbenzyl; thecompound of formula (IIa) wherein R²² is 3-aminobenzyl and R²³ is 3-(CH₃NHC(═O)NH)benzyl; the compound of formula (IIa) wherein R²² is 3-(CH₃NHC(═O)NH)benzyl and R²³ is 3-(CH₃ NHC(═O)NH)benzyl; the compound offormula (IIa) wherein R²² is 3-(N-methylamino)benzyl and R²³ is4-hydroxymethylbenzyl; the compound of formula (IIa) wherein R²² is3-((N,N-dimethylaminoglycyl)amino)benzyl and R²³ is3-((N,N-dimethylaminoglycyl)amino)benzyl; the compound of formula (IIa)wherein R²² is 3-((N-methylaminoglycyl)amino)benzyl and R²³ is3-((N-methylaminoglycyl)amino)benzyl; the compound of formula (IIa)wherein R²² is 3-((N,N-dimethylaminoglycyl)amino)benzyl and R²³ is4-hydroxymethylbenzyl; the compound of formula (IIa) wherein R²² is3-((N-phenylmethoxycarbonylaminoglycyl)amino)benzyl and R²³ is3-((N-phenylmethoxycarbonylaminoglycyl)amino)benzyl; the compound offormula (IIa) wherein R²² is 3-(glycylamino)benzyl and R²³ is3-(glycylamino)benzyl; the compound of formula (IIa) wherein R²² is3-(glycylamino)benzyl and R²³ is 4-hydroxymethylbenzyl; the compound offormula (IIa) wherein R²² is3-((N-phenylmethoxycarbonylamino-L-alanyl)amino)benzyl and R²³ is3-((N-phenylmethoxycarbonylamino-L-alanyl)amino)benzyl; the compound offormula (IIa) wherein R²² is3-((N-phenylmethoxycarbonylamino-L-phenylalanyl)amino)benzyl and R²³ is3-((N-phenylmethoxycarbonylamino-L-phenylalanyl)amino)benzyl; thecompound of formula (IIa) wherein R²² is 3-(L-alanyl)amino)benzyl andR²³ is 3-(L-alanyl)amino)benzyl; the compound of formula (IIa) whereinR²² is 3-(L-phenylalanyl)amino)benzyl and R²³ is3-(L-phenylalanyl)amino)benzyl; the compound of formula (IIa) whereinR²² is 5-hydroxy-1-pentyl and R²³ is hydrogen; the compound of formula(IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³ is 2-naphthylmethyl; thecompound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³ isbenzyl; the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyland R²³ is 4-hydroxymethylbenzyl; the compound of formula (IIa) whereinR²² is 6-hydroxy-1-hexyl and R²³ is 2-naphthylmethyl; the compound offormula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³ is3-hydroxybenzyl; the compound of formula (IIa) wherein R²² is5-hydroxy-1-pentyl and R²³ is (5-methylsulfonyl)-1-pentyl; the compoundof formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³ is 5-(CH₃S(O))-1-pentyl; the compound of formula (IIa) wherein R²² is5-hydroxy-1-pentyl and R²³ is cyclopropylmethyl; the compound of formula(IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³ is 5-methoxy-1-pentyl;the compound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³is 3-cyanobenzyl; the compound of formula (IIa) wherein R²² is5-hydroxy-1-pentyl and R²³ is 3-carboethoxybenzyl; the compound offormula (IIa) wherein R²² is 4-hydroxy-1-hexyl and R²³ is4-hydroxy-1-hexyl; the compound of formula (IIa) wherein R²² is4-hydroxy-1-hexyl and R²³ is 2-naphthylmethyl; the compound of formula(IIa) wherein R²² is 4-oxime-1-hexyl and R²³ is 4-oxime-1-hexyl; thecompound of formula (IIa) wherein R²² is 5-hydroxy-1-pentyl and R²³ is3-hydroxymethylbenzyl; the compound of formula (IIa) wherein R²² is6-amino-1-hexyl and R²³ is 4-hydroxymethylbenzyl; the compound offormula (IIa) wherein R²² is 3-(N,N-diethylaminocarbonyl)benzyl and R²³is 3-(N,N-diethylaminocarbonyl)benzyl; the compound of formula (IIa)wherein R²² is 3-carbomethoxybenzyl and R²³ is3-(N,N-diethylaminocarbonyl)benzyl; the compound of formula (IIa)wherein R²² is 3-carbomethoxybenzyl and R²³ is3-(N-ethylaminocarbonyl)benzyl; the compound of formula (IIa) whereinR²² is 3-hydroxymethylbenzyl and R²³ is hydrogen; the compound offormula (IIa) wherein R²² is 3-hydroxymethylbenzyl and R²³ is3-(N,N-diethylaminocarbonyl)benzyl; the compound of formula (IIa)wherein R²² is 3-hydroxymethylbenzyl and R²³ is3-(N-ethylaminocarbonyl)benzyl; the compound of formula (IIa) whereinR²² is 3-(N-propylaminocarbonyl)benzyl and R²³ is3-(N-propylaminocarbonyl)benzyl; the compound of formula (IIa) whereinR²² is 3-(HO₂ C)benzyl and R²³ is 3-(N-isopropylaminocarbonyl)benzyl;the compound of formula (IIa) wherein R²² is 3-(HO₂ C)benzyl and R²³ is3-(N-propylaminocarbonyl)benzyl; the compound of formula (IIa) whereinR²² is 3-(HO₂ C)benzyl and R²³ is benzyl; the compound of formula (IIa)wherein R²² is 3-(HO₂ C)benzyl and R²³ is cyclopropylmethyl; thecompound of formula (IIa) wherein R²² is 4-hydroxymethylbenzyl and R²³is 3-(HO₂ C)benzyl; the compound of formula (IIa) wherein R²² is3-hydroxymethylbenzyl and R²³ is 3-pyridinylmethyl; the compound offormula (IIa) wherein R²² is 4-hydroxymethylbenzyl and R²³ is3-aminocarbonylbenzyl; the compound of formula (IIa) wherein R²² is3-aminobenzyl and R²³ is 2-naphthylmethyl; the compound of formula (IIa)wherein R²² is cyclopropylmethyl and R²³ is 3-aminocarbonylbenzyl; thecompound of formula (IIa) wherein R²² is 3-aminocarbonylbenzyl and R²³is hydrogen; the compound of formula (IIa) wherein R²² is3-hydroxymethylbenzyl and R²³ is 3-(N-ethylaminocarbonyl)benzyl; thecompound of formula (IIa) wherein R²² is 3-hydroxymethylbenzyl and R²³is 3-(N-methylamino)benzyl; the compound of formula (IIa) wherein R²² is3-(N-methylamino)benzyl and R²³ is 2-naphthylmethyl; the compound offormula (IIa) wherein R²² is 4-formylbenzyl and R²³ is4-hydroxymethylbenzyl; the compound of formula (IIa) wherein R²² is3-(1-hydroxy-1-ethyl)benzyl and R²³ is 3-(1-hydroxyethyl)benzyl; thecompound of formula (IIa) wherein R²² is 3-pyridinylmethyl and R²³ is4-hydroxymethylbenzyl; the compound of formula (IIa) wherein R²² is3-(N-imidazolylmethyl)benzyl and R²³ is 3-(N-imidazolylmethyl)benzyl;the compound of formula (IIa) wherein R²² is3-(2,2-dimethyl-1-propionyl)benzyl and R²³ is3-(2,2-dimethyl-1-propionyl)benzyl; the compound of formula (IIa)wherein R²² is 3-(2,2,2-trifluoro-1-hydroxyethyl)benzyl and R²³ is3-(2,2,2-trifluoro-1-hydroxyethyl)benzyl; the compound of formula (IIa)wherein R²² is 3-(2-imidazolyl-C(═O))benzyl and R²³ is3-(2-imidazolyl-C(═O))benzyl; the compound of formula (IIa) wherein R²²is 3-(3-hydroxy-1-propyn-1-yl)benzyl and R²³ is3-(3-hydroxy-1-propyn-1-yl)benzyl; the compound of formula (IIa) whereinR²² is 3-(2,2,2-trifluoroacetyl)benzyl and R²³ is3-(2,2,2-trifluoroacetyl)benzyl; the compound of formula (IIa) whereinR²² is 3-propionylbenzyl and R²³ is 3-propionylbenzyl; the compound offormula (IIa) wherein R²² is 3-(4-pyrazolyl)benzyl and R²³ is3-(4-pyrazolyl)benzyl; the compound of formula (IIa) wherein R²² is3-(CH₃ CH₂ C(═N--OH))benzyl and R²³ is 3-(CH₃ CH₂ C(═N--OH))benzyl; thecompound of formula (IIa) wherein R²² is 3-sulfonamidobenzyl and R²³ is3-sulfonamidobenzyl; the compound of formula (IIa) wherein R²² is 3-(CF₃CH₂ C(═N--OH))benzyl and R²³ is 3-(CF₃ CH₂ C(═N--OH))benzyl; thecompound of formula (IIa) wherein R²² is 4-fluoromethylbenzyl and R²³ is4-fluoromethylbenzyl; the compound of formula (IIa) wherein R²² is4-(1-hydroxyethyl)benzyl and R²³ is 4-(1-hydroxyethyl)benzyl; thecompound of formula (IIa) wherein R²² is3-(5-methyl-1,2,3-oxadiazolyl)benzyl and R²³ is3-(5-methyl-1,2,3-oxadiazolyl)benzyl; the compound of formula (IIa)wherein R²² is 3-(H₂ NC(═NOH)benzyl and R²³ is 3-(H₂ NC(═NOH)benzyl; thecompound of formula (IIa) wherein R²² is 3-(H₂ NC(═NOH)-4-fluorobenzyland R²³ is 3-(H₂ NC(═NOH)-4-fluorobenzyl; the compound of formula (IIa)wherein R²² is 5-benzotriazolylmethyl and R²³ is 5-benzotriazolylmethyl;the compound of formula (IIa) wherein R²² is 5-benzimidazolylmethyl andR²³ is 5-benzimidazolylmethyl; the compound of formula (IIa) wherein R²²is 5-benzimidazolylmethyl and R²³ is 5-benzimidazolylmethyl; thecompound of formula (IIa) wherein R²² is 5-benzotriazolylmethyl and R²³is 4-hydroxymethylbenzyl; the compound of formula (IIa) wherein R²² is5-benzotriazolylmethyl and R²³ is 3-(3-pyrazolyl)benzyl; the compound offormula (IIa) wherein R²² is 5-indazolylmethyl and R²³ is5-indazolylmethyl; the compound of formula (IIa) wherein R²² is3-chloro-5-indazolylmethyl and R²³ is 3-chloro-5-indazolylmethyl; thecompound of formula (IIa) wherein R²² is 3-methylamino-5-indazolylmethyland R²³ is 3-methylamino-5-indazolylmethyl; the compound of formula(IIa) wherein R²² is 3-ethylamino-5-indazolylmethyl and R²³ is3-ethylamino-5-indazolylmethyl; the compound of formula (IIa) whereinR²² is 6-indazolylmethyl and R²³ is 6-indazolylmethyl; the compound offormula (IIa) wherein R²² is 3-amino-5-benzisoxazolylmethyl and R²³ is3-amino-5-benzisoxazolylmethyl; the compound of formula (IIa) whereinR²² is 5-(2-aminobenzoxazolyl and R²³ is 5-(2-aminobenzoxazolyl.
 10. Apharmaceutical composition of claim 1, wherein the compound is acompound of formula (IIaa): ##STR117## or a pharmaceutically acceptablesalt form thereof wherein: R⁴ and R⁷ are independently selected from:benzyl, methylbenzyl, dimethylbenzyl, ethylbenzyl, fluorobenzyl,pyrrolylmethyl, methoxybenzyl, isobutyl, nitrobenzyl, aminobenzyl,hydroxybenzyl, thienylmethyl, pyridylmethyl, or naphthylmethyl;R²² andR²³ are independently selected from:hydrogen, allyl, methyl, ethyl,propyl, cyclopropylmethyl, n-butyl, i-butyl, CH₂ CH═C(CH₃)₂,pyridinylmethyl, methallyl, n-pentyl, i-pentyl, hexyl, benzyl,isoprenyl, propargyl, picolinyl, methoxyethyl, cyclohexylmethyl,dimethyl-butyl, ethoxyethyl, methyl-oxazolinylmethyl, naphthylmethyl,methyloxazolinylmethyl, vinyloxyethyl, pentafluorobenzyl,quinolinylmethyl, carboxybenzyl, chloro-thienyl, benzyloxybenzyl,phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl, methoxybenzyl,methylbenzyl, ethoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl,aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl, allyloxybenzyl,fluorobenzyl, difluorobenzyl, chlorobenzyl, chloromethylbenzyl,fluoromethylbenzyl, iodobenzyl, bromobenzyl, cyclobutylmethyl,formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl, (H₂ NC(═O))-benzyl,carbomethoxybenzyl, carboethoxybenzyl, tetrazolylbenzyl, anddimethylallyl, aminomethylbenzyl, (O-benzyl-formaldoxime)benzyl,(O-methyl-formaldoxime)benzyl, (CH₃ O₂ CO)-benzyl, (HOCH₂ CH₂N═CH)-benzyl, N-benzylaminocarbonylbenzyl, N-methylaminobenzyl,N-ethylaminobenzyl, N-ethylaminomethylbenzyl, acetylbenzyl,acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethyl-boronic acid,N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH₃C(═NOH))-benzyl, (H₂ NNHC(═O))-benzyl, (H₂ NC(═O)NHN═CH)-benzyl, (CH₃ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH₃ NHC(═O))-benzyl,N,N-dimethylaminocarbonylbenzyl, (HOCH₂ CH(OH)CH₂ O)-benzyl,hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl,(hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl,(methylthio)benzyl, (methylsulfonyl)benzyl,N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl,glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl,(N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl,(N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH₃ CH₂NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl,N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl,N,N-diisopropylaminocarbonylbenzyl, N, N-di-n-propylaminocarbonylbenzyl,(hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H₂NSO₂)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H₂NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl,methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl,propionylbenzyl, butyrylbenzyl, (CH₃ CH₂ C(═NOH))-benzyl,(trifluorohydroxyethyl)benzyl, (CF₃ C(═NOH))-benzyl,(N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl,(benzyl-NHC(═O)O)benzyl, (CH₃ NHC(═O)O)benzyl, (NH₂ C(═O)CH₂ O)benzyl,(NH₂ C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl,(imidazolylmethyl)benzyl, ((CH₃)₃ C--C(═O))benzyl,(N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl,(pyrrolidinylethyl)aminocarbonylbenzyl,(piperidinylethyl)aminocarbonylbenzyl, (H₂ NC(═NOH))benzyl, (H₂NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl,indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl,thienylmethyl, furylmethyl.
 11. A pharmaceutical composition of claim10, wherein the compound, or a pharmaceutically acceptable salt formthereof, is selected from the group consisting of:the compound offormula (IIaa) wherein R⁴ and R⁷ are isobutyl, R²² and R²³ arecyclopropylmethyl; the compound of formula (IIaa) wherein R⁴ and R⁷ areisobutyl, R²² and R²³ are allyl; the compound of formula (IIaa) whereinR⁴ is 4-nitrobenzyl, R⁷ is 2-nitrobenzyl, R²² and R²³ arecyclopropylmethyl; the compound of formula (IIaa) wherein R⁴ and R⁷ are4-nitrobenzyl, R²² and R²³ are cyclopropylmethyl; the compound offormula (IIaa) wherein R⁴ is 4-nitrobenzyl, R⁷ is 2-nitrobenzyl, R²² andR²³ are n-butyl; the compound of formula (IIaa) wherein R⁴ is4-aminobenzyl, R⁷ is 2-aminobenzyl, R²² and R²³ are cyclopropylmethyl;the compound of formula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²²and R²³ are 3-hydroxybenzyl; the compound of formula (IIaa) wherein R⁴and R⁷ are 4-fluorobenzyl, R²² and R²³ are cyclopropylmethyl; thecompound of formula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²² andR²³ are 4-hydroxymethylbenzyl; the compound of formula (IIaa) wherein R⁴and R⁷ are 4-fluorobenzyl, R²² and R²³ are 3-aminocarbonylbenzyl; thecompound of formula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²² andR²³ are 3-acetylbenzyl; the compound of formula (IIaa) wherein R⁴ and R⁷are 4-fluorobenzyl, R²² and R²³ are 3-butyrylbenzyl; the compound offormula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²² and R²³ are3-hydroxymethylbenzyl; the compound of formula (IIaa) wherein R⁴ and R⁷are 4-fluorobenzyl, R²² and R²³ are 3-(CH₃ C(═N--OH)benzyl; the compoundof formula (IIaa) wherein R⁴ and R⁷ are 3-methoxybenzyl, R²² and R²³ arebenzyl; the compound of formula (IIaa) wherein R⁴ and R⁷ are4-fluorobenzyl, R²² and R²³ are 3-(H₂ NC(═NOH)benzyl; the compound offormula (IIaa) wherein R⁴ and R⁷ are 4-fluorobenzyl, R²² and R²³ are3-(H₂ NC(═NOH)-4-fluorobenzyl; the compound of formula (IIaa) wherein R⁴and R⁷ are 3-methoxybenzyl, R²² and R²³ are cyclopropylmethyl; thecompound of formula (IIaa) wherein R⁴ and R⁷ are 3-methoxybenzyl, R²²and R²³ are 4-hydroxymethylbenzyl; the compound of formula (IIaa)wherein R⁴ and R⁷ are 3-methoxybenzyl, R²² and R²³ are 3-methoxybenzyl;the compound of formula (IIaa) wherein R⁴ and R⁷ are 3-hydroxybenzyl,R²² and R²³ are 3-hydroxybenzyl; the compound of formula (IIaa) whereinR⁴ and R⁷ are 4-methoxybenzyl, R²² and R²³ are cyclopropylmethyl; thecompound of formula (IIaa) wherein R⁴ and R⁷ are 4-methoxybenzyl, R²²and R²³ are benzyl; the compound of formula (IIaa) wherein R⁴ and R⁷ are4-methoxybenzyl, R²² and R²³ are 2-naphthylmethyl; the compound offormula (IIaa) wherein R⁴ and R⁷ are 4-methoxybenzyl, R²² and R²³ are4-hydroxymethylbenzyl; the compound of formula (IIaa) wherein R⁴ and R⁷are 4-hydroxybenzyl, R²² and R²³ are benzyl; the compound of formula(IIaa) wherein R⁴ and R⁷ are 4-methoxybenzyl, R²² and R²³ are allyl; thecompound of formula (IIaa) wherein R⁴ and R⁷ are4-(2-hydroxyethoxy)benzyl, R²² and R²³ are benzyl; the compound offormula (IIaa) wherein R⁴ and R⁷ are 4-(2-morpholinylethoxy)benzyl, R²²and R²³ are benzyl; the compound of formula (IIaa) wherein R⁴ and R⁷ are3-(H₂ NC(═O)CH₂ O)benzyl, R²² and R²³ are n-butyl; the compound offormula (IIaa) wherein R⁴ and R⁷ are 3,4-difluorobenzyl, R²² and R²³ are3-hydroxymethylbenzyl; the compound of formula (IIaa) wherein R⁴ and R⁷are 3,4-difluorobenzyl, R²² and R²³ are 4-hydroxymethylbenzyl; thecompound of formula (IIaa) wherein R⁴ and R⁷ are 3,4-difluorobenzyl, R²²and R²³ are 3-(H₂ NC(═O))benzyl; the compound of formula (IIaa) whereinR⁴ and R⁷ are 3,4-difluorobenzyl, R²² and R²³ are 3-(H₂ NC(═NOH))benzyl;the compound of formula (IIaa) wherein R⁴ and R⁷ are 2-naphthylmethyl,R²² and R²³ are benzyl; the compound of formula (IIaa) wherein R⁴ and R⁷are 2-naphthylmethyl, R²² and R²³ are cyclopropylmethyl; the compound offormula (IIaa) wherein R⁴ and R⁷ are 2-thienylmethyl, R²² and R²³ arecyclopropylmethyl; the compound of formula (IIaa) wherein R⁴ and R⁷ are2-thienylmethyl, R²² and R²³ are 3-(H₂ NC(═NOH))benzyl; the compound offormula (IIaa) wherein R⁴ and R⁷ are 4-methylthiobenzyl, R²² and R²³ arebenzyl; the compound of formula (IIaa) wherein R⁴ and R⁷ are isopropyl,R²² and R²³ are n-hexyl; the compound of formula (IIaa) wherein R⁴ andR⁷ are 4-pyridylmethyl, R²² and R²³ are benzyl.
 12. A pharmaceuticalcomposition of claim 1, wherein the compound is a compound of formula(IIb): ##STR118## or a pharmaceutically acceptable salt form thereofwherein: R²² and R²³ are independently selected from the groupconsisting of:hydrogen, allyl, methyl, ethyl, propyl, cyclopropylmethyl,n-butyl, i-butyl, CH₂ CH═C(CH₃)₂, pyridinylmethyl, methallyl, n-pentyl,i-pentyl, hexyl, benzyl, isoprenyl, propargyl, picolinyl, methoxyethyl,cyclohexylmethyl, dimethyl-butyl, ethoxyethyl, methyl-oxazolinylmethyl,naphthylmethyl, methyloxazolinylmethyl, vinyloxyethyl,pentafluorobenzyl, quinolinylmethyl, carboxybenzyl, chloro-thienyl,benzyloxybenzyl, phenylbenzyl, adamantylethyl, cyclopropylmethoxybenzyl,methoxybenzyl, methylbenzyl, ethoxybenzyl, hydroxybenzyl,hydroxymethylbenzyl, aminobenzyl, formylbenzyl, cyanobenzyl, cinnamyl,allyloxybenzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl,chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl, bromobenzyl,cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl, nitrobenzyl,(H₂ NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl,tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl,(O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH₃ O₂CO)-benzyl, (HOCH₂ CH₂ N═CH)-benzyl, N-benzylaminocarbonylbenzyl,N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl,acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethyl-boronicacid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH₃C(═NOH))-benzyl, (H₂ NNHC(═O))-benzyl, (H₂ NC(═O)NHN═CH)-benzyl, (CH₃ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH₃ NHC(═O))-benzyl,N,N-dimethylaminocarbonylbenzyl, (HOCH₂ CH(OH)CH₂ O)-benzyl,hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl,(hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl,(methylthio)benzyl, (methylsulfonyl)benzyl,N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl,glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl,(N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl,(N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH₃ CH₂NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl,N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl,N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl,(hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H₂NSO₂)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H₂NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl,methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl,propionylbenzyl, butyrylbenzyl, (CH₃ CH₂ C(═NOH))-benzyl,(trifluorohydroxyethyl)benzyl, (CF₃ C(═NOH))-benzyl,(N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl,(benzyl-NHC(═O)O)benzyl, (CH₃ NHC(═O)O)benzyl, (NH₂ C(═O)CH₂ O)benzyl,(NH₂ C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl,(imidazolylmethyl)benzyl, ((CH₃)₃ C--C(═O))benzyl,(N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl,(pyrrolidinylethyl)aminocarbonylbenzyl,(piperidinylethyl)aminocarbonylbenzyl, (H₂ NC(═NOH))benzyl, (H₂NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl,indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl,thienylmethyl, furylmethyl.
 13. A pharmaceutical composition of claim12, wherein the compound, or a pharmaceutically acceptable salt formthereof, is selected from the group consisting of:the compound offormula (IIb) wherein R²² is 4-hydroxybenzyl and R²³ is 4-hydroxybenzyl;the compound of formula (IIb) wherein R²² is cyclopentylmethyl and R²³is cyclopentylmethyl; the compound of formula (IIb) wherein R²² isn-butyl and R²³ is n-butyl; the compound of formula (IIb) wherein R²² is3-hydroxybenzyl and R²³ is 3-hydroxybenzyl; the compound of formula(IIb) wherein R²² is 3-aminobenzyl and R²³ is 3-aminobenzyl; thecompound of formula (IIb) wherein R²² is cyclohexylmethyl and R²³ iscyclohexylmethyl; the compound of formula (IIb) wherein R²² iscyclobutylmethyl and R²³ is cyclobutylmethyl; the compound of formula(IIb) wherein R²² is 3-hydroxymethylbenzyl and R²³ is3-hydroxymethylbenzyl; the compound of formula (IIb) wherein R²² is3-formylbenzyl and R²³ is 3-formylbenzyl; the compound of formula (IIb)wherein R²² is 3-formaldoximebenzyl and R²³ is 3-formaldoximebenzyl. 14.A pharmaceutical composition of claim 1, wherein the compound is acompound of formula (Ibb): ##STR119## or a pharmaceutically acceptablesalt form thereof wherein: R²² and R²³ are independently selected fromthe group consisting of:hydrogen, allyl, methyl, ethyl, propyl,cyclopropylmethyl, n-butyl, i-butyl, CH₂ CH═C(CH₃)₂, pyridinylmethyl,methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl,picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl,methyl-oxazolinylmethyl, naphthylmethyl, methyloxazolinylmethyl,vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl,chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl,cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl,hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl,cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl,chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl,bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl,nitrobenzyl, (H₂ NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl,tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl,(O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH₃ O₂CO)-benzyl, (HOCH₂ CH₂ N═CH)-benzyl, N-benzylaminocarbonylbenzyl,N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl,acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethyl-boronicacid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH₃C(═NOH))-benzyl, (H₂ NNHC(═O))-benzyl, (H₂ NC(═O)NHN═CH)-benzyl, (CH₃₀NHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH₃ NHC(═O))-benzyl,N,N-dimethylaminocarbonylbenzyl, (HOCH₂ CH(OH)CH₂ O)-benzyl,hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl,(hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl,(methylthio)benzyl, (methylsulfonyl)benzyl,N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl,glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl,(N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl,(N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH₃ CH₂NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl,N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl,N,N-diisopropylaminocarbonylbenzyl, N, N-di-n-propylaminocarbonylbenzyl,(hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H₂NSO₂)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H₂NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl,methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl,propionylbenzyl, butyrylbenzyl, (CH₃ CH₂ C(═NOH))-benzyl,(trifluorohydroxyethyl)benzyl, (CF₃ C(═NOH))-benzyl,(N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl,(benzyl-NHC(═O)O)benzyl, (CH₃ NHC(═O)O)benzyl, (NH₂ C(═O)CH₂ O)benzyl,(NH₂ C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl,(imidazolylmethyl)benzyl, ((CH₃)₃ C--C(═O))benzyl,(N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl,(pyrrolidinylethyl)aminocarbonylbenzyl,(piperidinylethyl)aminocarbonylbenzyl, (H₂ NC(═NOH))benzyl, (H₂NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl,indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl,thienylmethyl, furylmethyl.
 15. A pharmaceutical composition of claim14, wherein the compound, or a pharmaceutically salt form thereof, isselected from the group consisting of:the compound of formula (Ibb)wherein R²² is benzyl and R²³ is hydrogen; the compound of formula (Ibb)wherein R²² is cyclopropylmethyl and R²³ is cyclopropylmethyl; thecompound of formula (Ibb) wherein R²² is benzyl and R²³ is benzyl; thecompound of formula (Ibb) wherein R²² is 3-hydroxybenzyl and R²³ is3-hydroxybenzyl; the compound of formula (Ibb) wherein R²² is3-hydroxymethylbenzyl and R²³ is 3-hydroxymethylbenzyl; the compound offormula (Ibb) wherein R²² is 4-hydroxybenzyl and R²³ is 4-hydroxybenzyl;the compound of formula (Ibb) wherein R²² is 3-methoxybenzyl and R²³ is3-methoxybenzyl; the compound of formula (Ibb) wherein R²² is3-(H2NC(═NOH))benzyl and R²³ is 4-hydroxymethylbenzyl; the compound offormula (Ibb) wherein R²² is 3-(H2NC(═NOH))benzyl and R²³ is3-(H2NC(═NOH))benzyl; the compound of formula (Ibb) wherein R²² is3-(H2NC(═NOH))-4-fluorobenzyl and R²³ is 3-(H2NC(═NOH))-4-fluorobenzyl.16. A pharmaceutical composition of claim 1, wherein the compound is acompound of formula (IId): ##STR120## or a pharmaceutically acceptablesalt form thereof wherein: R²² and R²³ are independently selected fromthe group consisting of:hydrogen, allyl, methyl, ethyl, propyl,cyclopropylmethyl, n-butyl, i-butyl, CH₂ CH═C(CH₃)₂, pyridinylmethyl,methallyl, n-pentyl, i-pentyl, hexyl, benzyl, isoprenyl, propargyl,picolinyl, methoxyethyl, cyclohexylmethyl, dimethyl-butyl, ethoxyethyl,methyl-oxazolinylmethyl, naphthylmethyl, methyloxazolinylmethyl,vinyloxyethyl, pentafluorobenzyl, quinolinylmethyl, carboxybenzyl,chloro-thienyl, benzyloxybenzyl, phenylbenzyl, adamantylethyl,cyclopropylmethoxybenzyl, methoxybenzyl, methylbenzyl, ethoxybenzyl,hydroxybenzyl, hydroxymethylbenzyl, aminobenzyl, formylbenzyl,cyanobenzyl, cinnamyl, allyloxybenzyl, fluorobenzyl, difluorobenzyl,chlorobenzyl, chloromethylbenzyl, fluoromethylbenzyl, iodobenzyl,bromobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl,nitrobenzyl, (H₂ NC(═O))-benzyl, carbomethoxybenzyl, carboethoxybenzyl,tetrazolylbenzyl, and dimethylallyl, aminomethylbenzyl,(O-benzyl-formaldoxime)benzyl, (O-methyl-formaldoxime)benzyl, (CH₃ O₂CO)-benzyl, (HOCH₂ CH₂ N═CH)-benzyl, N-benzylaminocarbonylbenzyl,N-methylaminobenzyl, N-ethylaminobenzyl, N-ethylaminomethylbenzyl,acetylbenzyl, acetoxybenzyl, N-hydroxylaminobenzyl, phenylmethyl-boronicacid, N-hydroxylaminomethylbenzyl, (hydroxyl)ethylbenzyl, (CH₃C(═NOH))-benzyl, (H₂ NNHC(═O))-benzyl, (H₂ NC(═O)NHN═CH)-benzyl, (CH₃ONHC(═O))-benzyl, (HONHC(═O))-benzyl, (CH₃ NHC(═O))-benzyl,N,N-dimethylaminocarbonylbenzyl, (HOCH₂ CH(OH)CH₂ O)-benzyl,hydroxyethoxybenzyl (oxazolidinyl)-benzyl, (hydroxyl)hexyl, hexenyl,(hydroxy)octyl, (hydroxyl)pentyl, (carboxy)pentyl, (carbomethoxy)pentyl,(methylthio)benzyl, (methylsulfonyl)benzyl,N,N-dimethylaminomethylbenzyl, N-methylaminomethylbenzyl,glycylaminobenzyl, N,N-dimethylglycylaminobenzyl, alanylaminobenzyl,(N-phenylmethoxycarbonyl)alanylaminobenzyl, phenylalanylaminobenzyl,(N-phenylmethoxycarbonyl) phenylalanylaminobenzyl, (CH₃ CH₂NHC(═O))-benzyl, N,N-diethylaminocarbonylbenzyl,N-ethylaminocarbonylbenzyl, N-propylaminocarbonylbenzyl,N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl,(hydroxypropynyl)benzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl, (H₂NSO₂)-benzyl, dihydroxyethylbenzyl, (MeHNC(═O)NH)-benzyl, (H₂NC(═O)NH)-benzyl, (HC(═O)NH)-benzyl, methanesulfonylpentyl,methoxypentyl, N-formyl-N-methylaminobenzyl, acetylaminobenzyl,propionylbenzyl, butyrylbenzyl, (CH₃ CH₂ C(═NOH))-benzyl,(trifluorohydroxyethyl)benzyl, (CF₃ C(═NOH))-benzyl,(N-methylglycyl)aminobenzyl, ((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl,(benzyl-NHC(═O)O)benzyl, (CH₃ NHC(═O)O)benzyl, (NH₂ C(═O)CH₂ O)benzyl,(NH₂ C(═NH))benzyl, ((N-phenylmethoxycarbonyl)glycylamino)benzyl,(imidazolylmethyl)benzyl, ((CH₃)₃ C--C(═O))benzyl,(N-methyl-N-ethylaminoethyl)aminocarbonylbenzyl,(pyrrolidinylethyl)aminocarbonylbenzyl,(piperidinylethyl)aminocarbonylbenzyl, (H₂ NC(═NOH))benzyl, (H₂NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl,indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl,thienylmethyl, furylmethyl.
 17. A pharmaceutical composition of claim16, wherein the compound, or a pharmaceutically acceptable salt formthereof, is selected from the group consisting of:the compound offormula (IId) wherein R²² is 4-hydroxymethylbenzyl and R²³ is4-hydroxymethylbenzyl; the compound of formula (IId) wherein R²² is3-hydroxybenzyl and R²³ is 3-hydroxybenzyl; the compound of formula(IId) wherein R²² is cyclopropylmethyl and R²³ is cyclopropylmethyl; thecompound of formula (IId) wherein R²² is 2-naphthylmethyl and R²³ is2-naphthylmethyl; the compound of formula (IId) wherein R²² is4-hydroxybenzyl and R²³ is 4-hydroxybenzyl; the compound of formula(IId) wherein R²² is 3-aminobenzyl and R²³ is 3-aminobenzyl; thecompound of formula (IId) wherein R²² is 3-hydroxymethylbenzyl and R²³is 3-hydroxymethylbenzyl; the compound of formula (IId) wherein R²² is3-(Me₂ NCH₂ C(═O)NH)-benzyl and R²³ is 3-(Me₂ NCH₂ C(═O)NH)-benzyl; thecompound of formula (IId) wherein R²² is 3-formaldoximebenzyl and R²³ is3-formaldoximebenzyl; the compound of formula (IId) wherein R²² is3-(CH₃ C(═N--OH))-benzyl and R²³ is 3-(CH₃ C(═N--OH))-benzyl; thecompound of formula (IId) wherein R²² is 3-(2-amino-4-thienyl)benzyl andR²³ is 3-(2-amino-4-thienyl)benzyl; the compound of formula (IId)wherein R²² is 5-hydroxypentyl and R²³ is 5-hydroxypentyl; the compoundof formula (IId) wherein R²² is 6-hydroxypentyl and R²³ is6-hydroxypentyl; the compound of formula (IId) wherein R²² is5-hydroxypentyl and R²³ is 2-naphthylmethyl; the compound of formula(IId) wherein R²² is 5-hydroxypentyl and R²³ is 4-hydroxymethylbenzyl;the compound of formula (IId) wherein R²² is 5-hydroxypentyl and R²³ is3-hydroxymethylbenzyl.
 18. A pharmaceutical composition of claim 1,wherein the compound is a compound of formula (IIa): ##STR121## or apharmaceutically acceptable salt form thereof, wherein: R²² is selectedfrom:cyclopropylmethyl, n-butyl, allyl, benzyl, naphthylmethyl,carboxybenzyl, methoxybenzyl, hydroxybenzyl, hydroxymethylbenzyl,(1-hydroxy-2-propyl)benzyl, aminobenzyl, formylbenzyl, cyanobenzyl,3-methylbutyl, 2-methylpropyl, n-pentyl, 3-N-N-dimethylaminobenzyl,3,4-methylenedioxybenzyl, pyridinylmethyl, pyridinylethyl, fluorobenzyl,difluorobenzyl, cyclobutylmethyl, formaldoximebenzyl, cyclopentylmethyl,nitrobenzyl, (H₂ NC(═O))-benzyl, carbomethoxybenzyl,N,N-dimethylaminobenzyl, carboethoxybenzyl, N-benzylaminocarbonylbenzyl,N-methylaminobenzyl, N-ethylaminobenzyl, N-propylaminobenzyl,N-butylaminobenzyl, acetylbenzyl, (CH₃ C(═NOH))-benzyl,N-methylaminocarbonylbenzyl, N,N-diethylaminocarbonylbenzyl,N,N-dimethylaminocarbonylbenzyl, (hydroxyl)hexyl, (hydroxyl)pentyl,(methylthio)benzyl, glycylaminobenzyl, N,N-dimethylglycylaminobenzyl,alanylaminobenzyl, (CH₃ CH₂ NHC(═O))-benzyl,N,N-diethylaminocarbonylbenzyl, N-ethylaminocarbonylbenzyl,N-propylaminocarbonylbenzyl, N,N-diisopropylaminocarbonylbenzyl, N,N-di-n-propylaminocarbonylbenzyl, (imidazolyl-C(═O))-benzyl,(pyrazolyl-C(═O))-benzyl, 3-phenylalanylaminobenzyl,3-(N-methylglycyl)aminobenzyl, 3-(CH₃ C(═NOH))benzyl,2-amino-5-benzoxazolylmethyl, 3-amino-5-benzisoxazolylmethyl,3-methylamino-5-indazolylmethyl, 3-ethylamino-5-indazolylmethyl,3,4-dihydroxybenzyl, (pyridylmethylaminocarbonyl)benzyl,(oxadiazolyl)benzyl, trifluoroacetylbenzyl, (pyrazolyl)benzyl,acetylaminobenzyl, (CH₃ CH₂ C(═NOH))-benzyl, (CF₃ C(═NOH))-benzyl,((4-morpholino)ethyl)aminocarbonylbenzyl,(N,N-dimethylaminoethyl)aminocarbonylbenzyl,(N,N-diethylaminoethyl)aminocarbonylbenzyl,(4-methylpiperazin-1-ylethyl)aminocarbonylbenzyl, (NH₂ C(═NH))benzyl,(imidazolylmethyl)benzyl, (pyrrolidinylethyl)aminocarbonylbenzyl,(piperidinylethyl)aminocarbonylbenzyl, (H₂ NC(═NOH))benzyl, (H₂NC(═NOH))fluorobenzyl, benzimidazolylmethyl, benzotriazolylmethyl,indazolylmethyl, benzoxazolinylmethyl, benzisoxazolylmethyl,thienylmethyl, thiazolylmethyl, thiazolylethyl, furylmethyl; and R²³ isselected from:naphthylmethyl, hydroxymethylbenzyl,(1-hydroxy-2-propyl)benzyl, aminobenzyl, acetylbenzyl, (CH₃C(═NOH))-benzyl, (pyrazolyl)benzyl, (CH₃ CH₂ C(═NOH))-benzyl, (CF₃C(═NOH))-benzyl, (H₂ NC(═NOH))benzyl, (H₂ NC(═NOH))fluorobenzyl,benzimidazolylmethyl, benzotriazolylmethyl, indazolylmethyl,benzoxazolinylmethyl, benzisoxazolylmethyl.
 19. A pharmaceuticalcomposition of claim 1, wherein the compound is a compound of formula(IIa): ##STR122## or a pharmaceutically acceptable salt form thereof,selected from the group consisting of:the compound of formula (IIa)wherein R²² is 3-aminobenzyl and R²³ is 3-aminobenzyl; the compound offormula (IIa) wherein R²² is 3-(CH₃ C(═NOH))benzyl and R²³ is 3-(CH₃C(═NOH))benzyl; the compound of formula (IIa) wherein R²² is 3-(H₂NC(═NOH)-4-fluorobenzyl and R²³ is 3-(H₂ NC(═NOH)-4-fluorobenzyl; thecompound of formula (IIa) wherein R²² is 3-(H₂ NC(═NOH)benzyl and R²³ is3-(H₂ NC(═NOH)benzyl; the compound of formula (IIa) wherein R²² is3-(3-pyrazolyl)benzyl and R²³ is 3-(3-pyrazolyl)benzyl; the compound offormula (IIa) wherein R²² is 5-indazolylmethyl and R²³ is5-indazolylmethyl; the compound of formula (IIa) wherein R²² is3-chloro-5-indazolylmethyl and R²³ is 3-chloro-5-indazolylmethyl; thecompound of formula (IIa) wherein R²² is 3-methylamino-5-indazolylmethyland R²³ is 3-methylamino-5-indazolylmethyl; the compound of formula(IIa) wherein R²² is 3-ethylamino-5-indazolylmethyl and R²³ is3-ethylamino-5-indazolylmethyl; the compound of formula (IIa) whereinR²² is 6-indazolylmethyl and R²³ is 6-indazolylmethyl; the compound offormula (IIa) wherein R²² is 3-amino-5-indazolylmethyl and R²³ is3-amino-5-indazolylmethyl; the compound of formula (IIa) wherein R²² is3-methoxycarbonyl-5-indazolylmethyl and R²³ is3-methoxycarbonyl-5-indazolylmethyl.
 20. A pharmaceutical composition ofclaim 1, wherein the compound is a compound of formula (IIa): ##STR123##or a pharmaceutically acceptable salt form thereof.
 21. A pharmaceuticalcomposition of claim 1, wherein the compound is a compound selected fromthe following formulae: ##STR124## or a pharmaceutically acceptable saltform thereof, wherein: R⁴ and R⁷ are independently selected from thefollowing groups:hydrogen; C₁ -C₃ alkyl substituted with 0-1 R¹¹ ; R⁵ is--OR²⁰ ; R⁶ is hydrogen or --OR²¹ ; R²⁰ and R²¹ are hydrogen; R¹¹ isselected from one or more of the following:H; halogen; --OR¹³ ; C₃ -C₁₀cycloalkyl substituted with 0-2 R¹² ; C₁ -C₄ alkyl substituted with 0-2R¹² ; aryl(C₁ -C₃ alkyl) substituted with 0-2 R¹² ; aryl substitutedwith 0-2 R¹² ; or a heterocyclic ring system selected from pyridyl,pyrimidinyl, triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, tetrazolyl, benzofuranyl, indolyl, quinolinyl,isoquinolinyl, oxazolidinyl, said heterocyclic ring system beingsubstituted with 0-2 R¹² ; R¹², when a substituent on carbon, isselected from one or more of the following:benzyloxy, halogen, methyl,C₁ -C₄ alkoxy, CF₃, 2-(1-morpholino)ethoxy, --CO₂ H, hydroxamic acid,hydrazide, --C(R¹⁴)═N(OR¹⁴), cyano, boronic acid, sulfonamide, formyl,C₃ -C₆ cycloalkoxy, C₁ -C₄ alkyl substituted with --NR¹³ R¹⁴, --NR¹³R¹⁴, hydroxy, hydroxymethyl; or R¹², when a substituent on nitrogen, ismethyl; R¹³ is H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, or benzyl; R¹⁴ is OH, H,CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, NH₂, C₂ -C₄ alkenyl, or benzyl; R¹³and R¹⁴ can alternatively join to form --(CH₂)₄ --, --(CH₂)₅ --, --CH₂CH₂ N(R¹⁵)CH₂ CH₂ --, or --CH₂ CH₂ OCH₂ CH₂ --; R¹⁵ is H or CH₃ ; R²²and R²³ are independently selected from the following:hydrogen; C₁ -C₈alkyl substituted with 0-3 R³¹ ; C₂ -C₆ alkenyl substituted with 0-3 R³¹; C₂ -C₄ alkynyl substituted with 0-3 R³¹ ; R³¹ is selected from one ormore of the following:halogen, --OR¹³, C₁ -C₄ alkyl, C₃ -C₁₀ cycloalkyl,--C(R¹⁴)═N(OR¹⁴), --CO₂ R¹³, --S(O)_(m) R¹³ ; aryl substituted with 0-5R³² ; or a heterocyclic ring system chosen from pyridyl, pyrimidinyl,triazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,tetrazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl,oxazolidinyl, said heterocyclic ring being substituted with 0-2 R³² ;R³², when a substituent on carbon, is selected from one or more of thefollowing:benzyloxy, halogen, 2-(1-morpholino)ethoxy, --CO₂ R¹³,hydroxamic acid, --CONR¹³ NR¹³ R¹⁴, cyano, boronic acid, sulfonamide,--CHO, C₃ -C₆ cycloalkoxy, --NR¹³ R¹⁴, --C(R¹⁴)═N(OR¹⁴), NO₂, --OR¹³,--NR⁴⁰ R⁴¹, --SO_(m) R¹³, --SO_(m) NR¹³ R¹⁴, --C(═O)NR¹³ R¹⁴,--OC(═O)NR¹³ R¹⁴, --C(═O)R¹¹, --OC(═O)R¹¹, --OCO₂ R¹³, phenyl,--C(═O)NR¹³ --(C₁ -C₄ alkyl)--NR¹³ R¹⁴, --C(═O)NR⁴⁰ R⁴¹, C₁ -C₄haloalkyl, C₁ -C₄ haloalkoxy, C₂ -C₄ haloalkenyl, C₁ -C₄ haloalkynyl,--C(═O)NR¹³ R¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ NR¹⁴ ;--C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ;--C(═O)--(C₁ -C₄ alkyl)--NR¹³ CO₂ R¹³ ; or C₁ -C₄ alkoxy substitutedwith 0-3 groups selected from: R¹¹, C₃ -C₆ cycloalkyl, --C(═O)NR¹³ R¹⁴,--NR¹³ R¹⁴ or OH; C₁ -C₄ alkyl substituted with 0-3 groups selectedfrom: R¹¹, ═NR¹⁴, ═NNR¹³ C(═O)NR¹³ R¹⁴ or --NR¹³ R¹⁴ ; C₂ -C₄ alkenylsubstituted with 0-3 R¹¹ ; C₂ -C₄ alkynyl substituted with 0-3 R¹¹ ; a5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatomsindependently selected from oxygen, nitrogen or sulfur substituted with0-2 R¹² ; R³², when a substituent on nitrogen, is methyl; m is 0, 1, or2; R⁴⁰ is selected from: H, C₁ -C₃ alkyl; R⁴¹ is selectedfrom:--C(═O)NR¹³ R¹⁴ ; --C(═O)NR¹³ NR¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ R¹⁴ ;--C(═O)C(R¹¹)₂ NR¹³ NR¹⁴ ; --C(═O)C(R¹¹)₂ NR¹³ CO₂ R¹³ ; --C(═O)H;--C(═O)R¹¹ ; --C(═O)--(C₁ -C₄ alkyl)--NR¹³ R¹⁴ ; --C(═O)--(C₁ -C₄alkyl)--NR¹³ CO₂ R¹³ ; or - 3amino acids linked together via amidebonds, and linked to the N atom via the carboxylate terminus.